Influence of blood flow on intestinal absorption of drugs and nutrients

Phannac. Ther.Vol. 6, pp, 333--393, 1979.

Specialist Subject Editors:

Pergamon Press Ltd. Printed in Great Britain

W. FORTH a n d W. RUMMEL

INFLUENCE OF BLOOD FLOW ON INTESTINAL ABSORPTION OF DRUGS AND NUTRIENTS D. WINNE Abteilung flir Molekularpharmakologie, Pharmakologisches Institut der Universitiit, Wilhelrnstrasse 56, D - 7 4 0 0 Tfibingen, Federal Republic Germany

1. INTRODUCTION In pharmacokinetics, gastrointestinal absorption, or more precisely the transfer from the gastrointestinal depot into the central compartment, is characterized by one coefficient: the invasion constant (Dost, 1968, p. 33) or the apparent first-order absorption rate constant (Gibaldi and Perrier, 1975, p. 33; Notari, 1975, p. 78; Wagner, 1975, p. 63). This coefficient summarizes all factors which influence gastrointestinal absorption. One of these factors is the blood flow in the stomach and the intestine. In this review the influence of blood flow on intestinal absorption is described. An attempt is made to explain the different experimental results by a simple model with several modifications. Previously, the same topic has been reviewed by Varr6 (1966), Mao and Jacobson (1970), Ther and Winne (1971), Winne (1971b and c), and Eade (1976a and b). Most experiments in this field are carried out on animals; only deductive conclusions can be drawn in relation to gastrointestinal absorption in man. 2. METHODS 2.1. PRINCIPLES In order to investigate the influence of blood flow on intestinal absorption it is necessary to measure the absorption rate at different blood flow rates. Therefore, the rate of intestinal blood flow rate has to be varied quantitatively. 2.1.1. Absorption Rate

Absorption rate is by definition the net transfer of fluid and solutes per unit of time from lumen into the blood and/or the lymph (Fig. 1). It can be determined by measuring the disappearance rate from the intestinal lumen and/or the appearance rates in the intestinal venous blood and in the lymph. Under certain artificial conditions the appearance rate in the serosal bath or 'serosal sweat' is measured instead. Sometimes it is necessary to take into account the accumulation or uptake rate in the intestinal tissue and the rate of metabolism. The metabolites can be determined in the intestinal lumen, tissue, blood, lymph, and the serosal bath. One has to be aware that occasionally a decomposition of the substance in the intestinal lumen and the adsorption to mucus and the cell surface might interfere. According to the experimental condition and the investigated substance, one or more of the components listed above can be neglected. The rates have the dimension amount per time and the units are therefore mole or g per hr, min, or sec. Often the rates are standardized by relating them to easily measurable quantities such as wet tissue weight, dry weight, length, serosal surface etc. The absorption rates may vary with time or along the intestinal loop according to the mode of administration of the substances. Using the single pass per~usion of the ~PT Vol. 6. No. 2--H

333

334

D. W|NNE Luminal Inflow

Arterial Inflow

DisappearanCef Lumenrom Intestinal L en

Luminal Outflow

Intestinal TL~ue

[~//~

i

Appearance@II Intestinal venous Blood

Serosal Bath in al e,th

venous Outflow

FIG. I. The intestinal absorption rates.

intestinal lumen, a steady state is reached after an initial period i.e. the absorption rate remains .constant, if secondary changes do not interfere. The local absorption rate might decrease from the inflow to the outflow cannula, if as a consequence of the absorption an appreciable decrease of the intraluminal concentration results. A spatial concentration gradient along the loop does not exist, if a substance is injected into the intestinal lumen (single administration). In this case a gradient can develop in the radial direction since the fluid in the lumen remains unstirred. Furthermore, the luminal concentration is reduced continuously due to the absorption. Therefore, the absorption rate decreases with time provided that the transport mechanisms are not saturated. The experimental design can be extended to repeated administrations, if after each absorption period the intestinal lumen is emptied. The amount absorbed in the second period and in further periods should be equal, if the conditions and the length of the periods are not changed. The first period differs from the following ones, since at the beginning of the first period the intestinal tissue does not contain residuals of the absorbed substance from preceding periods. If a solution is recirculated through the lumen of an intestinal loop (recirculation), the concentration decreases as after a single administration. Since samples can be taken several times, the time course of the luminal concentration and of the absorption rate can easily be investigated. In the case of an exponential decrease the absorption can be characterized by the first-order absorption rate constant (dimension: 1/time; units: hr -~, min -~, sec -~) which is obtained from a semilogarithmic plot of the data. The concentration gradient along the intestinal loop can be neglected, since the recirculation rate is usually high. With regard to the temporal or spatial change of the absorption rates the measured rates are average values. This fact has to be taken into account when different analyses are compared. Methods for studying intestinal absorption in animals have been reviewed by Wilson (1962), Levin (1967), Parsons (1968), Levine (1971), Smyth (1974) and Pfleger (1975). 2.1.2. Blood Flow Rate When analysing the relationship between intestinal absorption and blood flow, attention should be paid to the method used for measuring the blood flow rate. The region of absorption should correspond with the region where the blood flow is measured. If the blood flow rate is determined from a larger region (e.g. total portal flow rate), one has to be aware that the pattern of the blood tiow in different parts of the intestine differ. In that case changes in the overall blood flow rate may or may not parallel the blood flow changes in the region of absorption. Furthermore, changes of the total blood flow in an intestinal loop do not always correspond with changes of the mucosal flow rate. Different absorption rates may result due to a difference of blood

Influence of blood flow on intestinal absorption of drugs and nutrients

335

distribution in the intestinal wall in spite of the fact that the total flow rate does n o t differ. The mucosal blood flow can be determined by measuring the absorption of highly permeable substances, or the blood-to-lumen flux of barbital, or by the microsphere-method (Table 1). Analogously, the gastric muscosal blood flow is determined by measuring the secretion rate of suitable substances (Lanciault and Jacobson, 1976, Jacobson, 1968). The methods for measuring the blood flow in general have been reviewed by Kramer et al. (1963), Lanciault and Jacobson (1976), Svanvik and Lundgren (1977). In the following description only those methods are considered which have been used to investigate the dependence of intestinal absorption on blood flow. TABLE 1. Methods for Determining the Mucosal Blood Flow Rate in the Intestine By measurement the absorption of: krypton 13 xenon 107, 176 carbon monoxide 21, 30, 66, 197 tritiated water 45, 186, 190 By measurement the blood-to-lumen flux of barbital 37 By microspheres 7, 22, 29, 59, 60, 104, 113, 197, 235, 267, 307 Numbers refer to references at end.

2.2. ARTIFICIAL VASCULAR PERFUSION OF INTESTINAL LOOP The vascularly perfused intestinal loop is suitable to investigate the influence of blood flow on intestinal absorption. It enables the experimenter to vary the blood flow and to measure the absorption and the blood flow rate simultaneously. But this method is not simple and it requires experience. The perfusion techniques of isolated organs in general have been summarized by Ross (1972). Table 2 summarizes a series of investigations in which the vascularly perfused intestinal loop has been used. For further references see Parsons and Pilchard (1968). The references in Table 2 are subdivided according to several technical details of the method and to the species used. Under the heading 'vascularly perfused' all methods are summarized where the natural arterial blood supply to the intestinal loop is interrupted in some way. The vascularly perfused loop has been used to study the intestinal absorption and metabolism as well as the hemodynamics and related topics or the conditions for transplantation (Salerno et al., 1966; Johnson et al., 1969). The influence of blood flow on intestinal absorption has been investigated in more detail by Williams et ai. (1964), Ochsenfahrt (1973), Pytkowski and Lewartowski (1972), Lee (1973), Boyd (1977), Boyd and Parsons (1978). Single experiments have been performed by Parsons and Prichard (1968), Parsons and Powis (1971), Boyd et al. 0975). The small intestine of dogs and rats has been used mainly for the vascular perfusion of a loop. Further methods for frogs, toads, rabbits, and cats have been described. Also the colon can be vascularly perfused. The intestine is perfused in situ with (Windmueller and Spaeth, 1972, 1977) or without cannulating the lymph vessels. After cannulation of the blood and lymph vessels the excised intestinal segment can be stored in a humid chamber or can be placed in a bath with saline solutions or paraffin oil. Then the 'serosal sweat' can be collected in the paraffin oil bath (Lee, 1973) or the humid chamber separately from the intestinal lymph, otherwise the 'serosal sweat' and the lymph are collected together (Fisher and Gardner, 1974b). If the venous effluent is not collected separately, a mixture of venous effluent, lymph, and 'serosal sweat' is obtained (Parsons and Prichard, 1968). If the serosal bath contains a large volume of saline solution, the permeation of water into the bath can hardly be measured, since the volume change is too small. Under particular conditions--

Vascular perfusion rate given by

Vascular perfusion medium

Mode of mounting

Organ used

Species

Arterio-venous pressure difference, arterial pressure adjusted by Pump + bypass Gas pressure in reservoir Hydrostatic pressure in reservoir Arterial pressure of donor animal Arterial pressure of the same animal

Pumping rate

Diluted blood Erythrocytes + artificial plasma Saline, plasma expander

Blood

in s~u

Saline bath Paraffin bath Humid chamber

+ Other organs Colon

Small intestine

139, 214, 215, 318, 319

125

34,48,49, 56, 63,79,80, 81, 111, 112, 115, 116, 120, 149, 155, 229, 264, 265, 282, 316, 318, 319

79, 80, 81 48, 49, 67, 111, 112, 120, 149, 229, 264, 265 63, 115, 125, 135, 155, 229, 282

34, 56, 116, 139, 162, 214, 215, 316, 318, 319

125, 214, 215, 316 162, 229 48,49, 63, 79,80, 81, !15, 120, 135, 139, 149, 155, 264,265, 282 34, 56,67, 79,80, 81, 111, 112, 116, 318, 319

28, 239

109, 138

Rat 34, 48, 49, 56, 63, 67, 79, 80, 81, 111, 112, 115, !16, 120, 125, 139, 149, 155, 162, 214, 215, 264, 265, 282 135, 316, 318, 319 229

135 67, 162

136, 137

136, 137

136, 137

136, 137

Cat

279

91, 92, 117, 195, 205, 247, 268, 277, 313

117

28, 92, 109, 138, 195, 239, 247, 277, 279, 313 268 91, 117, 205

91,92, 138, 195, 239, 268 28, 109,205, 277, 279, 313

117, 247,279

268

28, 91, 92, 109, 117, 138, 195, 205, 239, 247, 277, 279, 313

Dog

TAnLE.2. Methods Using an Artificial Vascular Pe~usion of Intestinal Loop

76

76

76

76

Rabbit

23, 25, 26, 27, 230

23, 25, 26, 27, 230

23, 25,26 27

230

23, 25, 26, 27, 230

Frog toad

t~

z z

O,

Absorption Single or repeated luminal administration Luminal recirculation Luminal infusion Single pass perfusion Metabolism Hemodynamics and related topics 28, 109, 138, 277, 279

91

91, 92, 117, 195, 205, 239, 247, 3i3

92, 109, 117, 138, 195,205, 239, 277 28, 91, 92, 195, 239, 247, 279

Open recirculation

single pass

268, 313

Closed recirculation

Numbers refer to references at end.

Topic of investigation

Mode of vascular perfusion

136 136, 137

136

136, 137

111, 112, 120, 155, 316, 318, 319 115, 116, 135, 162, 282

48~ 49, 56, 63, 149, 229, 264, 265

316, 318, 319

34, 111, !12, 214, 215, 229

67, 79, 80, 81, 125, 139, 162, 318, 319

48, 49, 56, 63, 67, 115, 125, 162, 214, 215, 229, 264, 265, 282

34, 79,80, 81, 116, 120, 135, 139, 149, 155, 316, 318, 319 111,112, 229

76

76

23, 25, 26, 27, 230

230

23, 25, 25, 27, 230

--d

e~

~o

o

O

O"

0

0

o-

¢t

¢t

338

D. W1NNE

provided the outflow from the blood vessels is collected separately--the concentration change in the serosal bath, e.g. due to the permeation of a xenobiotic through the intestinal wall, can also be determined (Ochsenfahrt, 1971b, 1973). The disappearance rate is obtained from the change of amount in the intestinal lumen or from the change of luminal concentration corrected for water net flux by means of a marker. The simultaneous perfusion of a saline solution and moist oxygen/carbon dioxide through the intestinal lumen--segmented flow (Fisher and Gardner, 1974a and b)--improves the oxygen supply, when blood is not used as the vascular perfusion medium. Moreover, it increases the absorption rate by reducing the unstirred layer thickness. This method can be used also in vivo (Winne, 1976). The appearance rate in the intestinal venous blood is calculated from the vascular perfusion rate and the arterio-venous concentration difference. In addition, at the end of the experiment the uptake into the intestinal tissue can be measured (Ochsenfahrt, 1971b, 1973; Lamers and Hfilsmann, 1972). The vascularly perfused intestinal loop is especially suitable to study the blood-to-lumen flux of a substance, since a constant blood concentration can easily be maintained, if the vascular perfusate is not recirculated (Ochsenfahrt, 1976). The following vascular perfusion media have been used: blood from donor animals or from the same animal, diluted blood, erythrocytes in artificial plasma, and saline solutions with and without plasma expanders. The perfusate is recirculated in a closed or open circuit or the single pass perfusion is used. The flow rate can easily be determined by drop recording or measuring the perfusate volume (weight) collected periodically. If the vascular perfusate is infused by a pump directly into the intestinal artery, the arterial perfusion rate is identical with the pumping rate and the arterial pressure depends on the flow rate, the vascular resistance, and the venous pressure. Pumps which generate a pulsatile flow seem to be better, since a nonpulsatile blood flow to isolated intestine results in a decline of the blood pH, an increase of the venous lactate level, mesenteric hemorrhages, bleeding into the lumen, edema and cyanosis of the bowel within 6hr (Austen and McLaughlin, 1965). If the arterial pressure is adjusted by the height of the reservoir, by the gas pressure in a closed reservoir or if it is given by the arterial pressure of the donor animal or the pressure in the supplying artery (e.g. femoral artery) of the same animal, the vascular perfusion rate has to be measured, since the flow rate depends on the vascular resistance and on the arteriovenous pressure difference. The lack of central vasoconstrictor tone causes a low vascular resistance when the periarterial nerves are cut (Windmueller et al., 1970; Ochsenfahrt, 1973; Windmueller and Spaeth, 1977). The addition of dexamethasone together with norepinephrine to the vascular perfusate is recommended (Windmueller et al., 1970; Windmueller and Spaeth, 1972, 1977). It prevents a hyperemia. Thus, a normalisation of the vascular resistance and blood flow in the isolated intestinal loop can be achieved. Simultaneously hypersecretion, hypermotility, and an epithelial necrosis, which has been observed after 5 hr of perfusion, is prevented. Also the opposite, arteriolar spasms (Jacobs et al., 1966; Ochsenfahrt, 1973) or an initial period of vasoconstriction (Grenier et al., 1974) have been observed. Therefore, several substances have been added to the vascular perfusate to dilate the vessels: papaverine (Forth, 1967; Grenier et ai., 1967), xylocaine, cyproheptadine (Salerno et al., 1966), and phenoxybenzamine (Hohenieitner and Senior, 1969). Pentobarbital (WindmueUer et al., 1970; Windmueller and Spaeth, 1977; Lee, 1973) and cyproheptadine + atropine (Hohenleitner and Senior, 1969) reduce the intestinal motility; promethazine restores the normal water absorption(Forth, 1967). Sometimes a surfactant is added which prevents fat embolism and greatly reduces hemolysis (Miyauchi et al., 1966; Dubois et al., 1968; Roy et al., 1970; Roy and Dubois, 1972). Long lasting perfusions require the addition of antibiotics (Rinecker et al., 1970; Windmueller et al., 1970; Parsons and Powis, 1971; Windmueller and Spaeth, 1972, 1977). No additives are needed, if the blood from a donor animal is perfused directly into the intestinal artery without interruption by a pump (Windmueller et al., 1970; Ochsenfahrt, 1973; Windmueller and Spaeth, 1977).

Influenceof blood flowon intestinalabsorption of drugs and nutrients

339

2.3. INTESTINALLOOP WITHINTACTNATURALARTERIALBLOODSUPPLY In this section absorption methods are reviewed which use an intestinal loop with intact natural arterial blood supply. Table 3 summarizes investigations where these methods have been used to study the influence of blood flow on intestinal absorption in the small intestine of dogs, cats, rats, guinea pigs and rabbits. If the intestinal blood flow rate is measured by an electromagnetic flow meter placed around the mesenteric artery, the blood circulation remains closed. After insertion of a bubble flow meter into the portal vein the blood circulates in a closed system. The blood flow rate can also be measured by determining the cardiac output and the fractional blood flow to the intestinal loop. Since the intestinal absorption of some substances is blood flow limited, their clearance can be used to determine the effective mucosal blood flow rate (Table 1). But it should be kept in mind that by this method the blood flow rate is measured indirectly by an absorption process. If the vein of the intestinal loop is punctured, the venous effluent can be measured by drop recording or by determining the volume or weight of the collected blood. The blood can be reinfused (e.g. into the jugular vein) or the lost amount of blood must be replaced by blood from donor animals. The blood flow rate can be reduced by lowering the arterial pressure (screw clamp around the mesenteric artery, electrical stimulation of vasoconstrictor fibers) or by increasing the venous pressure (raising the venous outflow cannula). In the latter case the extracellular volume increases. A transmural electrical field stimulation increases the flow rate. Positive and negative changes of the flow rate can be obtained by administration of vasoactive drugs or by changing the systemic blood pressure (high or low infusion rate of donor blood). In some experiments the investigators confined themselves to recording the natural variability of the intestinal blood flow rate. The substances are injected (single or repeated administration) or continuously infused into the intestinal lumen. Luminal recirculation or single pass perfusion methods have also been applied. The disappearance rate is determined from the change of the solute concentration in the intestinal lumen. The appearance rate in the intestinal venous blood can be calculated, when samples of the intestinal venous blood and, if necessary, of the arterial blood are taken. This method has also been used without changing the blood flow rate to investigate the intestinal absorption (Matthews and Smyth, 1954; Duncan and Waton, 1968; Winne 1972c; Henning and Hird, 1972; Mottaz and Worbe, 1972; Galluser et al., 1976; Boyd and Parsons, 1976, 1978; Boyd, 1977) or the metabolism of drugs and nutrients (Kiyasu et al., 1956; Atkinson et al., 1957; Nienstedt and Hartiala, 1969; George et al., 1974; Bock and Winne, 1975; Windmueller and Spaeth, 1975; Josting et al., 1976; Hanson and Parsons, 1977). The absorption rate can also be calculated from the concentration curves in the systemic blood after intestinal and intravenous administration of a substance (Scholer and Code, 1954; Wagner and Nelson, i963; Dost, 1964; Dost, 1968, p. 155; Loo and Riegelman, 1968; Love et al., 1973; Gibaldi and Perrier, 1975, p. 130; Notari, 1975, p. 85; Wagner, 1975, p. 173). Love and co-workers (Love and Matthews, 1972; Love et al., 1972; Matthews and Love, 1974;Love, 1976) used this method to investigate the influence of blood flow on the unidirectional sodium fluxes in the small intestine of dogs. When substances are administered intravenously, the appearance in the intestinal lumen can be measured. In principle, the appearance rates in the lymph and in the intestinal blood can be investigated simultaneously, if additionally the lymph vessels are cannulated (Forth et al., 1969, 1970; Seebald and Forth, 1977). But in the methods listed in Table 3 this has not been done. 2.4. BLOOD FLOW RATE CHANGED BUT NOT MEASURED In Table 4 some investigations in dogs, cats and rats are listed where the blood flow rate has been changed but not measured. In these experiments where the substance was administered by gastric or oral feeding the site of absorption was the stomach and

Venous Weight or outflow volume Drop recorder Portal bubble flow meter Electromagnetic flow meter around mesenteric artery Cardiac output + fractional blood flow Luminal clearance of highly permeable substances

Constriction of mesenteric artery Changing systemic blood pressure Stimulation vasoconstrictor nerve fibers Transmural electrical field stimulation Changing venous pressure Drugs Natural variability

Single or repeated Recirculation Infusion

Blood flow measurement

Change of blood flow

Mode of luminal administration

With reinfusion Single pass

Closed

Blood circulation

Open

Small intestine

Absorption site

Species

35, 36, 165, 225, 240, 243, 300-304

165, 186, 225, 240, 243, 300

35, 36, 175, 177, 178, 193, 225, 240, 301-304

175, 177, 178, 186, 193

35, 36, 175, 177, 178, 193, 225, 240

243

165, 300-304

243, 300-304

35, 36, 165, 175, 177, 178, 186, 193, 225 300-304

35, 36, 165, 175, 177, 178, 186, 193, 225, 240, 243, 300-304

Dog

12, 16, 184, 287

287 12, 16, 133

12

184, 287

133, 184, 287

12, 16, 133, 184, 287

12, 16, 133, 184, 287

12, 16, 133, 184, 287

Cat

171,320, 329

II, 19,20

I 1, 19, 20, 320

171, 172, 213, 218, 219, 254, 269, 321, 326, 327, 329, 336

19, 20

I 1, 171, 172, 213, 218, 219, 254, 269, 320, 321,326, 327, 329, 336

11, 171, 172, 213, 218, 219, 254, 269, 320, 321,326, 327, 329, 336

19, 20

I1, 19, 20, 171, 172, 213, 218, 219, 254, 269, 320, 321,326, 327, 329, 336

Rat

95

95

95

95

95

Guinea pig

TABLE3. Methods for Investigation of the Relationship Between Absorption and Blood Flow in an Intestinal Loop with Intact Natural Arterial Blood Supply

5

21

5, 21

21

5

5

21

5, 21

Rabbit

Z Z gn

*After luminal and intravenous administration. Numbers refer to references at end.

Disappearance from lumen Appearance in intestinal venous blood Appearance in intestinal lumen Deconvolution of systemic blood concentration curves* 12, 16, 184, 287

240, 301

175, 177, 178, 193

165

133

35, 36, 186, 225, 243, 300-304 19, 20, 171, 172, 254, 269, 321,326, 329, 336 11, 171, 172, 213, 218, 219, 254, 269, 320, 326, 329, 336 1I, 327

171, 172, 213, 218, 219, 254, 269, 320, 321,326, 329, 336

Measured quantity

133 1I, 327

175, 177, 178, 186, 193

Substance offered from blood side

Single pass perfusion

95

5

5, 21

5

:3

lID

O.

o

O

ta

P-

~o

O

O

o

fD

342

D. WmNE TABLE 4. Methods for Investigation o f the Relationship Between Intestinal Absorption and Blood Flow When the Flow Rate is Changed but Not Measured

Species Absorption site

Change of blood flow

Small intestine Colon Gastrointestinal tract Compression of aorta Constriction of mesenteric artery Changing systemic blood pressure Drugs Partial obstruction of portal vein Ligation of portal vein

Dog

Cat

Rat

57, 204, 205

188

164, 222 275

231,278 204, 205 231,278 222 164, 222, 275 57

188 188

Experimental period

Short Long

204, 205 57, 231,278

188

164, 222, 275

Mode of administration

Single or repeated luminal administration Oral feeding Substance offered from blood side

57, 204, 205

188

164, 275

Measured quantity

Disappearance from lumen Appearance in intestinal lumen Deconvolution of systemic blood concentration curves* Systemic blood concentration

231,278 222 204, 205

188 222 164, 275

57, 231,278

*After luminal and intravenous administration. Numbers refer to references at end.

the small intestine. The blood flow rate was changed on the arterial side (compression of aorta, constriction of the superior mesenteric artery, changing the systemic blood pressure by infusion or withdrawal of blood, administration of vasoactive drugs) or on the venous side (partial obstruction or iigation of portal vein). In some investigations the reduction of the blood flow was maintained for a longer period--not only during an acute experiment. The absorption was measured by the disappearance rate or was calculated from the concentration curves in the systemic blood after intestinal and intravenous administration of the substance. In some cases only the systemic blood concentration was recorded. The permeation in the reverse direction was measured by

the appearance rate in the intestinal lumen. 2.5. MISCELLANEOUS METHODS

Levitt and Levitt 0973) investigated several models concerning the influence of b l o o d flow o n g a s t r o i n t e s t i n a l a b s o r p t i o n b y c o m p a r i n g t h e a b s o r p t i o n o f H2, H e , SF6, o r X e w i t h t h e a b s o r p t i o n o f CFL. T h e g a s e s w e r e i n t r o d u c e d i n t o t h e s t o m a c h , t h e small intestine, or the colon of rats and the expired air was analysed. 3. E X P E R I M E N T A L

DATA

3.1. DEPENDENCE OF VENOUS APPEARANCE ON BLOOD FLOW S o m e d a t a c o n c e r n i n g t h e n o r m a l b l o o d flow r a t e in t h e s m a l l i n t e s t i n e a n d c o l o n o f r a t s , d o g s a n d c a t s a r e s u m m a r i z e d in T a b l e s 5 a n d 6.

200--400 260 560

150-220 150-220

200--400 254 . 528

s = Standard deviation.

Colon

Proximal distal

Ileum

0.6 0.54 0.30

1.13 0.89

0.7 0.89 0.59

1.41

150-220

0.9 0.62 1.54 1.52

200--400 250 350-380

Jejunum

0.81 0.82 1.04 0.71

1.1

0.2 0.13 0.10

0.22 0.22

0.2 0.20 0.14

0.27

0.12

0.04

0.4

0.22 0.31 0.18

0.3

Blood flow rate mean s ml/min g

150-220

130-170 150-166 260 566

Small intestine

Proximal intermediate distal

200.-400

Duodenum

Body weight g

Rat

284 298 298

38 38

284 37 37

38

38

284 11 317

41 292 298 298

284

Ref

0.27-0.30 0.73 0.8 1.24

0.22 0.27 0.34 0.38 0.65 0.83 0.89

0.57 0.75 0.91 0.98 1.04 1.02 0.92

0.48 0.57 0.63 0.72

1.39 0.75

0.57

0.09

0.11 0.49 0.08 0.22

0.06

0.14 0.07 0.13 0.45 0.51 0.43

0.22

0.33 0.10

Blood flow rate mean s ml/min g

Dog

110 77 42 88

209 134 232 4 54 77 187

93 54 187 77 88 88 88

196 55 274 42

77 54

Ref

Cat

0.15-0.25 0.22 1.04

0.81

0.23 0.31 0.4--0.6 0.89

0.15-0.3 0.2 0.25 0.25-0.35 0.28 0.29 0.31 0.35 0.50 0.85

1.02

0.07

0.07 0.13

0.43

0.10 0.09 0.12 0.04

Blood flow rate mean s ml/min g

TAeLE 5. Normal Blood Flow Rate in Small Intestine and Colon of the Rat, Cat and Dog

121 122 86

86

245 246 65 86

285 144 15 96 123 272 12 97 14 90

86

Ref

o

O

O

Ig

to

S"

O

O

ar

O

g:

0.4 0.5

Rat

68 7 10.9

s=20 s=l s = 3.3

33-77 (31-88)*

170 s = 5 2 140-190 159 s = 50 284 s = 48 200-600 343 40-120

11.6 16.4

25

19 12.7

s = 3.7 s=6

s=4

Superior mesenteric artery ml/min ml/min kg b.w.

b.w. = body weight, s = standard deviation, * = coeliac artery.

Guinea pig

2.8 2.8-3.7 2.8-3.7 3-4.5 3-5

9-22 10-19 14-21 14-27 5-20 18-27 21-23

kg

Cat

Dog

Species

Body weight

90 89 89 259 260 261 311 263

202 35 276 238 289 315 339 73

Ref.

11-16 12-33

0.6--0.7

31-146 15--46 36 s = l l

841

Portal vein ml/min

0.2-0.28

1.3-4 2.2-4 2.2-4

20.7 24.2

Body weight kg

s = 5.4

I 1.4-52

20.7

ml/min kg b.w.

TABLE 6. Normal Blood Flow Rate Through Superior Mesenteric Artel~ and Portal Vein

95

223

89 69 272

9 271

Ref.

Z

Influence of blood flow on intestinal absorption of drugs and nutrients

345

Examples for the relationship between the appearance rate in the intestinal venous blood and the blood flow rate are shown in Figs. 2 and 3. The corresponding details are given in Tables 7 and 8. In these tables further investigations are listed where the same or similar relationships have been observed. In all examples the appearance rate is standardized by the luminal concentration: rate/concentration. The standardized absorption rate represents a clearance term with units of flow. Since at zero blood flow rate blood does not appear in the intestinal veins, the appearance rate of a substance in the intestinal venous blood is zero. Therefore, the curves for the appearance rate must intersect the axes at the origin. Dotted lines indicate the extrapolation of the curves towards the origin. This does not mean that at zero blood flow rate the substances do not enter the vascular bed. In fact, they penetrate into the capillaries, but because of the absence of blood flow they are not drained and do not appear in the venous vessels. The amount of substance which enters the vascular bed at zero blood flow rate is the excess of substance in the first drops of vascular effluent, when the vascular perfusion is started after a period of zero flow rate (Boyd, 1977; Boyd and Parsons, 1978). The appearance rate of krypton decreases linearly with decreasing venous outflow rate (Fig. 2a), if the mesenteric artery is constricted successively. The extrapolated line intersects the origin. In the range measured the appearance of digitoxin in the portal venous blood shows also a linear relationship to the portal flow rate (Fig. 2b). But the extrapolation to the origin results in a curve with a convex shape. A linearly extrapolated curve would intersect the abscissa at a positive value. The appearance rate of some other substances shows the same dependence on blood flow as krypton and digitoxin (Table 7). In contradiction to Fig. 2a--where the venous outflow was changed by a constriction of the mesenteric artery--the curve of the appearance rate a •

b

.o5-I. . | Krypton •o 4 1

cat

/

/'

,/

c .o,

l .." mllmin Ow'"':" , • , - , / 0 10 20 30 Portal Flow Rate

d mllmin.g Krypton

ml Irnin.g

.,, ~T~

•

Krypton

.10.+"

~.02 0

/~

°21

I.. mllmin-g 01" • , , , , , t 0 .I .2 .3 Venous Outflow Rate

'

I

.o~1 Dicjitoxin

.o,-I u')

.oe

""" '"""

.05. n-,llmin.g, /

Venous Outflow Rate

/ '" ,rnl/mi'n, g. /

Villous Flow Rate

FIG. 2. Examples f o r the dependence o f the appearance rate in the intestinal venous blood on blood flow rate. Appearance rate standardized by luminal concentration (d)/CL). In panels a and c appearance rate and venous outflow rate related to I g wet weight o f intestinal tissue. Bars indicate _ standard error. Dotted lines: extrapolation to zero flow rate. Panel a: venous outflow rate reduced by constriction o f mesenteric artery, data taken f r o m Svanvik (1973c); panel b: portal flow rate varied by natural variability, data taken from Haass et ol. (1972); panel c: venous outflow rate varied by changing venous pressure, data taken from Svanvik (1973c); panel d: venous outflow rate raised in intra-arterial infusion o f isoprenaline, see also Pig. 3(a). Villous blood flow rate was estimated f r o m the correlation between intestinal venous outflow and villous plasma flow obtained in a separate study (Biber et oL, 1973b). Appearance rate related to ] g intestinal tissue, villous blood flow rate to I g villous tissue. Data taken from Biber et ol. (1~/3c). Technical details and further experimental data showing similar relationships are given in Table 7.

346

D. WINNE

~" .15t

Krypton

i'°t

/¢

".10

,+/

~'.05

~[ , / / ¢ ~

] /;n,,oo

....'~/

.05

t /

rat

0 0.5 1.0 Venous Outflow Rate

0 0.5 1.0 1.5 Venous Outflow Rate

c

d

roll min.g .o4' nErythritol rat

' 'ml/min.g . Ribitol rat .03-

.04"

.03'

~ .0~" "

.0~'.t

.01""

<..01- .... -o C 0 0

ml I min.g , / ;

z

Venous Outflow Rate

0 0

...~

a

',

~l~ rrdImin.g , /

2

Venous Outflow Rate

FiG. 3. Examples for the dependence of the appearance rate in the intestinal venous blood on blood flow rate. Appearance rate standardized by luminal concentration (dP/CL). Venous outflow rate and appearance rate related to I g wet weight of intestinal tissue. Bars indicate + standard error. Dotted lines: extrapolation to zero flow rate. In panels b - d circles represent experiments with decreasing and squares with increasing flow rate. Panel a- venous outflow rate raised by intra-arterial infusion of isoprenaline, data taken from Biber et al. (1973c); panels b-d: venous outflow rate varied by raising or lowering systemic blood pressure, data taken from Ochsenfahrt and Winne (1969); Winne and Remischovsky (1971b). Technical details and further experimental data showing similar relationships are given in Table 8.

in Fig. 2c shows a c o n v e x shape when extrapolated to zero. This indicates that it makes a difference whether the venous outflow is changed by a constriction of the arterial supply or by an increase of the venous pressure. An increase of the intestinal blood flow by transmural electrical field stimulation results also in a c o n v e x curve. A c o n v e x curve with a concave extrapolated section is obtained if the appearance rate of krypton is increased b y an intra-arterial infusion of isoprenaline and is plotted vs the villous flow rate (Fig. 2d). This rate has been estimated from the correlation between venous outflow rate and villous plasma flow obtained in separate experiments (Biber et al., 1973b). The c o n v e x part becomes linear, if the appearance rate of krypton is plotted vs the venous outflow rate (Fig. 3a). In the rat the appearance rate of a series of substances increases nonlinearly with increasing blood flow rate and vice versa, so that concave curves result (Fig. 3b, Table 8). At higher blood flow rates the increase of the appearance rate is less than at lower rates. The appearance rate of erythritol and other substances increases only, if the blood flow rate is increased from low to intermediate values (Fig. 3c). The increase from 1 to 2 ml/min g is not accompanied b y a further increase of the appearance rate. The appearance o f ribitol in the jejunal blood of the rat is independent of the venous outflow rate in the range measured (Fig. 3d). The appearance rate of 3-O-methylglucose in the venous outflow of frog small intestine decreases linearly, when the vascular flow rate is lowered (Boyd, 1977; Boyd and Parsons, 1978). The linear extrapolation of the curve would intersect the ordinate at a positiv e value like the curve in Fig. 3a. This value corresponds to the amount of 3-O-methylglucose which enters the vascular bed at zero vascular flow rate (see abovb). In the presence of phlorizin the appearance rate of 3-O-methylglucose is considerably lower and independent of the vascular flow rate corresponding to Fig. 3d. Some further investigations are listed in Table 9. The appearance rate of labeled sodium in the intestinal venous blood increases when raising the vascular perfusion

Cat

Jejunum

Jejunum

Cat

Jejunum

Cat

Jejunum

Ileum

Dog

Cat

Small intest,

Small intest,

Rabbit

Dog

Jejunum

Rat

Small intest,

Jejunum

Dog

Guinea pig

Jejunum

Site of absorption

Cat

Species

Venous outflow

Venous outflow

Venous outflow

outflow

Venous

Magnetic flow meter

Portal bubble flow meter Venous outflow

Venous outflow

Venous outflow Venous outflow Venous outflow

Venous outflow pressure Transmural electrical field stimulation Isoprenaline i.a.

Secretin i.a.

Arterial pressure, motility Constriction mesent, artery, motility

Natural variability

Constriction mesent, artery Constriction mesent, artery System. blood pressure drugs i.v. Natural variability

Blood flow rate Measured by Changed by

1' Krypton

1" Krypton

~' Krypton

1' Krypton

~1' [D,L-phenyl- I ], / alanine / ( D,L-serine ~ [ L-phenyl- ] ~ | alanine [ ~ [.L-sefine j

~' Digltoxin digoxin

~ Salicylamid

~ Tritiated water

4[ Glucose

~ Krypton

Substance

~ 50 ~.Ci/ml

~tCi/ml

~ 50

~50 ~ Ci/mi

50.5 /zmol/ml 50 /zmol]ml ~ 50 p.Ci/ml

0.4-0.8 ~M

I mM

9 /~Ci/ml

~5"0 /~Ci/ml 5.4%

Luminal concentr,

Recircul.

Recircul.

Recircul.

Recircul.

Repeated administr.

Repeated administr.

Infusion

Single pass perfusion

Repeated administr. Single administr,

Recircul.

v

r

Mode of luminal administr,

16

12

287

12

240

239

95

5

320

301

287

Remarks references

Technical details of the examples diagrammed in Fig. 2 and further experimental data showing similar relationships, v = vascularly perfused loop, r = determined: change of appearance rate with time and rate constant, 1" = increased, ~ = decreased.

(2d)

(2c)

(2b)

(2a)

Fig.

TABLE 7. Dependence o f the Appearance Rate in Intestinal Venous Blood on Blood Flow Rate

e,

g~

O

E-.

O -t

o-

o ¢t

,-h

Venous outflow Venous outflow Venous outflow Venous outflow Venous outflow

Venous outflow Vascular perf. rate Venous outflow Vascular perf. rate Venous outflOW Venous outflow Venous outflow Venous outflow Venous outflow

Jejunum

Small intest,

Jejunum

Jejunum

•Jejunum

Jejunum

Jejunum

Jejunum

Small intest, Jejunum

Small intest, Jejunum

Jejunum

Jejunum

Jejunum

Jejunum

Cat

Frog

Rat

Rat

Rat

Rat

Rat

Rat

Frog

Frog

Rat

Rat

Rat

Rabbit

(3c)

Rat

Cat

Vascular perf. rate

Jejunum

Cat

(3a)

(3b)

Venous outflow Venous outflow

Site of absorption

Species

Fig.

System. blood pressure System. blood pressure System. blood pressure System. blood pressure System. blood pressure Drugs i.v. Inflow pressure Vascular perf. rate Cholecystokinin i.a. Vascular perf. rate System. blood pressure System. blood pressure System. blood pressure System. blood pressure Natural variability

Isoprenaline i.a. Sympathetic nerve fiber stimulation Vascular perf. rate

Blood flow rate Measured or given by Changed by

Krypton

Krypton

~

~

~'

~

0

Galactose + phlorizine Galactose + phlorizine Salicylamid glucuronid

Urea

Erythritol

Leucine

1' ~

Krypton

~

Tritiated water

Ethanol

Methanol

Amidopyrine

Aniline

Salicylic acid Glucose

~

~

~

~

~

0

~' 3-O-methylglucose

~

1'

Substance

100 ~tM 2 mM I00 mM 2 mM

11.6/£M

229/tM

~ 50 /zCi/ml endogen

I I.I mM

6.3/t]a

9 /t Ci/ml

34.3 I~M

37.6/tM

746 ~tM

170/~M

I mM

- 50 ~tCi/ml - 50 /t Ci/ml

Mode of Luminal concentr.

213, 219

Single pass per fusion Single pass per fusion Single pass perfusiun Single pass perfusion Single pass perfusion

Single pass perfusion Single pass perfusion Single pass perfusion Single pass perfusion Single pass perfusion

--

Single pass perfusion Recircul. r

s

v

v

27

Single pass v perfusion

Recircul.

287

Recircul.

5

172

172

335, 336

335, 336

25

12

23O

215

32O

335, 336 .

335, 336

213, 219

16

Remarks reference

Recircul.

Luminal administr.

TABLE 8. Dependence of the Appearance Rate in Intestinal Venous Blood on Blood Flow Rate

x z ~n

g

o,

.o_

<

Jejunum

Small intest,

Small intest,

Rat

Guinea pig

Frog

Venous outflow Venous outflow Venous outflow Portal bubble flow meter Vascular perf. rate Vascular perf. rate

System. blood pressure System. blood pressure System. blood pressure Natural variability ~

~'

~'

~

~'

3-O-methylglucose + phlorizine

Ouabain

Sorbose

Mannitol

Ribitol

50 pM

I mM

0.4-0.8 p.M

100 ttM

554 ttM

189 p.M

Single pass perfusion

Single pass perfusion Single administr. Single administr. Infusion v

27

95

W.

337

335, 337

Jejunum

Gastrointest, tract

GastroIntest. tract

Gastrointest, tract

Rat

Rat

Dog

Dog

Dog

Vascular perf. rate Vascular perf. rate Magnetic flow meter when setting constrict.

Permanent constriction portal vein

Permanent constriction mesent, artery

Vascular perf. rate Vascular perf. rate Permanent constriction mesent, artery T

1'

J-131triolein Xylose J-131albumin C-14-octanoate

Xylose J-131triolein J-131albumin Xylose

Iron

Sodium-22

Substance

v = vascularly perfused loop, T = increased, ~ = decreased, = no change.

Jejunum

Species

Blood flow rate Measured or given by Changed by

Mode of luminal administr,

Single administr, 0.18 Single tLmole/ml administr, 12 g Single oral 50 p.Ci feeding 4 weeks 50/~Ci after operation 8 g in Single oral 20 ml feeding 15/~Ci 1 week after in 50 ml operation 0.5 g/kg Single oral 50 ~Ci feeding 3-4 weeks 1-2 ttCi after operation

Luminal concentr, or dose

Systemic blood concentr.

Systemic blood concentration

Appearance venous blood Appearance venous blood Systemic blood concentr.

Measured quantity

278

1'

57 57 57

= =

231

231

278 278

67

87

Remarks References

= 1`

T

Effect

TABLE 9. Miscellaneous Data on the htfluence of Intestinal Blood Flow on the Appearance in the Intestinal or Systemic Venous Blood

Technical details of the examples diagrammed in Fig. 3 and further experimental data showing similar relationships, v = vascularly perfused loop, determined: rate constant of vascular outwash curves, s = administered: salicylamid (1 mM), 1' = increased, ~ = decreased, W. = Winne unpublished.

Jejunum

Jejunum

Rat

Rat

Site of absorption

r =

3d

O

-.t ¢

e~

Ig

e~

R

O

m.

O

O

R

e~ O

350

D. WINNE

rate. The appearance rate of iron, however, decreases under comparable conditions. After constriction of the mesenteric artery or the portal vein for a longer period the absorption tests with xylose, J~31-triolein and JI3~-albumin show different results. The concentration of the test substance in the systemic blood lies above, about, or below the level of control animals, or the level obtained in the pre-constriction period. The different results may be due to different postoperative periods. Figure 4a summarizes several curves for the dependence of the appearance rate on venous outflow rate obtained in the rat jejunum. It can easily be recognized that the dependence of absorption on blood flow rate decreases as the absorbability of the substances decreases. Tritiated water, here used as water soluble foreign substance, is absorbed at the highest rate and its appearance rate increases nearly linearly with increasing venous outflow rate. The limiting factor of the absorption is not the penetration through the epithelium but the drainage by blood: blood ]low limited absorption. On the other side, the appearance rate of sorbose is small and does not change between a blood flow rate of 0.3 and 1.7 ml/min g: blood ]low independent absorption. In this case the drainage by blood does not represent the limiting factor but the slow penetration through the epithelium. For substances which are absorbed at intermediate rates concave curves are obtained. The appearance rate increases as the venous outflow rate increases, but the increment decreases with increasing blood flow rate: the curves level off into a horizontal line. This horizontal section shifts to lower blood flow rates as the absorbability of the substances decreases.

.2;rnllmin. g

.21b rnllmin-g

4

'i / / ~'""""~

/

water

or.. Sorbose

0 I rnlrnin.g 2 Venous Outflow Rate

0 I mllmin-g 2 Venous Outflow Rate

FIG. 4. The dependence of the appearance rate in intestinal venous blood (panel a) and of the disappearance rate from intestinal lumen (panel b) on blood flow rate. Selected data obtained in rat jejunum. Appearance and disappearance rates standardized by luminal concentration (O/CL). Venous outflow rate, appearance and disappearance rates related to 1 g wet weight of intestinal tissue. Bars indicate±standard error. Data taken from Ochsenfahrt and Winne (1969), Winne and Remischovsky (1971a, b), Winne (1972a), Lichtenstein and Winne (1974), Winne (unpublished).

Figure 5a shows that the relationship between the appearance rate of krypton and the venous outflow rate depends on the mode of changing the flow rate. Curve 2 is obtained by increasing the blood flow rate by means of an intra-arterial infusion of isoprenaline, while curve 3 is the result of an infusion of secretin, and curve 4 is the effect of a transmural electrical field stimulation. The different course of curves 2 and 3 indicates that the 'effective' mucosai blood flow rate at high venous outflow rate is greater after the infusion of secretin than of isoprenaline (Fig. 5b). The blood distribution pattern in the intestinal wall is obviously different~ A transmural electrical field stimulation has about the same effect as a secretin infusion. The constriction of the mesenteric artery causes a decrease of the appearance rate proportionally to the decrease of the venous outflow (curve l). On the other hand, the stimulation of

Influence of blood flow on intestinal absorption of d r u g s a n d nutrients

351

b a

~

~

J_

,'7

3

"~

•

S~V7

4

Krypton

!

"6

=

f

.5 1.0 Venous Outflow Rate

0

0

.5 1.0 Venous Outflow Rate

FIG. 5. Dependence of krypton appearance rate in intestinal venous blood on blood flow rate and the mode of changing the flow rate. Panel a: appearance rate standardized by luminal concentration (~/CL); panel b: fraction of 'effective' blood flow rate (of intramural blood flow fully equilibrated with luminal fluid); venous outflow rate and appearance rate related to ! g wet weight of intestinal tissue. Bars indicate + standard error. Curve 1(O): constriction of mesentcric artery, curve 2(0): intra-arterial infusion of isoprenaline, curve 3(11): intra-arterial infusion of secretin, curve 4(A): transmural electrical field stimulation, curve 5(I-]): stimulation of sympathetic nerve fibers. Data taken from Biber et aL (1973c), Svanvik (1973c), Biber

(1974).

sympathetic nerve fibers reduces the venous outflow rate. The diminution of the appearance rate, however, is very small (curve 5), this means the blood flow rate in the capillaries draining the krypton is only slightly reduced. Therefore, the fraction of villous blood flow is increased (see Fig. 5b). By non-steady state experiments it has been shown that 3-0-methylglucose and amino acids in contrast to urea enter the vascular bed from two pools (compartments) with different rates (Boyd, 1977; Boyd and Parsons, 1978). After loading the mucosa initially with substrate from the lumen and after abruptly washing out the lumen the rate of appearance in the vascular effluent (unloading) decreases with time by a double exponential function. The rate constant for unloading of the fast component increases linearly with the vascular flow rate, while the rate constant of the slow component is independent of flow rate. It is supposed that the fast component clears the mucosal epithelium and the unstirred layer, while the slow component clears the tissue below the epithelium. The examples illustrated in Fig. 6 show' that the sequence of blood flow changes apparently influences the relationship between appearance rate and venous outflow rate. These results have been obtained by two similar methods for a number of drugs and nutrients (Table 10). In separate experiments the blood flow rate of a rat jejunal loop has been changed in three steps from high to low or from low to high values by decreasing or increasing the systemic blood pressure. The period Of high flow rate in one experiment corresponds to the period with low flow rate in the other; the intervals after starting the luminal perfusions are equal. In the experiments with decreasing blood flow rate the appearance rate decreases in all examples (Figs. 6a-d). But starting with a period of low blood flow rate the increase of the flow rate does not cause an increase of the antipyrine appearance rate to the level which is measured at high flow rate in the first period (Fig. 6a). For salicylic acid, L-phenylalanine, and galactose the divergence is greater: even more the appearance rate decreases though the blood flow rate is raised (Figs. 6b-d). The appearance rate of L-phenylalanine at low flow rate in the first period is higher than in the experiments where the same flow rate is adjusted in the third period. Thus, crossing curves are obtained (Fig. 6c). The crossing of the curves in the other examples is less marked.

D. W[NNE

352

b

a

"mUmin.g

,~

nl I m ~ . ~ ' ~

.10-

a,, ® U

c

f

~.05

Antipyrine r

at

cm

.05 :- Salicylic Acid rat ml/min.g

0

,

,

,

rnl / rain-g

I

c 'mlImin.g "~ .10 ,,/: iz

,

!

0 1 2 Venous Outflow Rate

/

0 I 2 Venous Outflow Rate d 'ml/min.g .10

Galactose rat

U

m

~.05

.05

Q. <

":

"0

;: :

0

L-Phenylalanine

rat

ml Imin .g , / 0 ; 2 Venous Outflow Rate

•"

rnll min.g ,

I

o { 2 Venous Outflow Rate

FiG. 6. Experimental examples for the dependence of the appearance rate in intestinal venous blood on decreasing and increasing blood flow rate. Venous outflow rate varied by raising or lowering systemic blood pressure. Appearance rate standardized by luminal concentration (¢b/CL). Venous outflow rate and appearance rate related to I g wet weight of intestinal tissue. Bars indicate ± standard error. Dotted lines: extrapolation to zero flow rate. Circles represent experiments with decreasing and squares with increasing flow rate, see also the arrows. Data taken from Ochsenfahrt and Winne (1969), Winne (1973), Lichtenstein and Winne (1974). Technical details and further experimental data showing similar relationships are given in Table 10.

3.2. DEPENDENCE OF LUMINAL DISAPPEARANCE ON BLOOD FLOW If the disappearance rate from the intestinal lumen is taken as the parameter for absorption, one has to keep in mind that at zero blood flow rate the disappearance rate does not approach zero, since in the absence of blood drainage the substances penetrate into the intestinal wall and appear at the serosal surface as shown in numerous in vitro experiments. The relationship between the disappearance rate and the blood flow rate is illustrated by four examples in Fig. 7. Technical details and further data are given in Table ll. The reduction of venous outflow rate decreases the disappearance rate of glycine from canine jejunum. The linear extrapolation of the curve intersects the ordinate at a positive value (Fig. 7a). After administration of sulfaethidole into the jejunum of the dog this substance disappears exponentially from the lumen. The rate constant obtained from a semilogarithmic plot becomes smaller, if the flow rate is reduced by stepwise constriction of the mesenteric artery (Fig. 7b). At zero flow rate the rate constant has a positive value: a small amount of sulfaethidole disappears from the jejunal lumen. A curve with concave shape describes the relationship between rate constant and flow rate in the superior mesenteric artery. The data of Table 12 demonstrate also that the reduction of the intestinal blood flow by different methods diminishes the disappearance rate of sodium, glucose, fluid, carbon dioxide, and hydrogen. The disappearance rate of galactose in the presence of phlorizin is independent of blood flow (Fig. 7c). Figure 7d shows the dependence of the unidirectional fluxes and the net flux of sodium through the mucosa of canine jejunum on blood flow. The unidirectional fluxes decrease as the flow rate in the superior mesenteric artery is reduced. The sodium net flux directed from the lumen to blood decreases at low flow rates until the direction changes.

Influence of blood flow on intestinal absorption of drugs and nutrients

353

TABLE 10. Dependence of the Appearance Rate in Rat Jejunal Blood on Decreasing and Increasing Venous Outflow Rate

Fig. (6a)

(6b)

(6c)

(6d)

Blood flow rate Changed by

Substance

Luminal concentr,

System. blood pressure System. blood pressure System. blood pressure Inflow pressure Inflow pressure

Antipyrine

13.5/./.M

benzoic acid Ethylene glycole 3-O-methylglucose Antipyrine

21.5/zM

System. blood pressure System. blood pressure System. blood pressure System. blood pressure System. blood pressure System. blood pressure System. blood pressure System. blood pressure

Salicylic acid Benzoic acid Amidopyrine

Remarks references

12.3/~M

Single pass perfusion Single pass perfusion Single pass perfusion Recircul.

v 215

14.2 ~M

Recircul.

v 215

32.2/zM

Single pass perfusion Single pass perfusion Single pass perfusion Single pass perfusion Single pass perfusion Single pass perfusion Single pass perfusion Recircul.

274 p.M

21.4/zM 746/zM

Glycerol

20/zM

Aniline

12/.tM

Antipyrine

329 ~M

o-phenyialanine L-phenyialanine

34.5/ZM

System. blood pressure System. blood pressure System. blood pressure System. blood pressure

L-phenylalanine Salicylic acid L-phenylalanine 3-O-methylglucose

31.1/~M 33.3 mM 12.8/zM

System. blood pressure System. blood pressure System. blood pressure Inflow pressure

Galactose 3-O-methylglucose 3-O-methylglucose L-phenylalanaine

Mode of luminal administr,

33.3 mM

213, 219 a 219 335, 337

213, 219 213, 219 a 219 335, 337 a 269 a 269 329 329

30.9 p.M

Single pass perfusion Single pass perfusion RecircuL

329

21.5 p.M

Recircul.

171

100 ~.M 100 mM 37.8/,~M 38 mM 27.3 mM

Single pass perfusion Single pass perfusion Recircui,

172 172 171 171 171

91.8/~M

Recircul.

a 269 329

v 215

Technical details of the examples diagrammed in Fig. 6 and further experimental data showing similar relationships. All data obtained in rat jejunum,blood flow rate measured by venous outflow, a = acidic luminal solution (pH 2.2 or 3), v = vascularly perfused loop. The relationship between the disaPpearance rate from the intestinal lumen and the v e n o u s o u t f l o w r a t e d e p e n d s o n t h e s e q u e n c e o f b l o o d flow c h a n g e . T h i s is e x e m p l i f i e d in Fig. 8 ( f o r f u r t h e r d a t a s e e T a b l e 13). T h e c u r v e s c o r r e s p o n d m o r e o r l e s s w i t h t h e c u r v e s o b t a i n e d f o r t h e a p p e a r a n c e r a t e ( c o m p a r e w i t h Fig. 6). T h e r e f o r e , a d e t a i l e d d e s c r i p t i o n is o m i t t e d . T h e b l o o d flow d e p e n d e n c e o f t h e d i s a p p e a r a n c e r a t e d e c r e a s e s a s t h e a b s o r b a b i l i t y o f t h e s u b s t a n c e s d e c r e a s e s (Fig. 4b). W h e n c o m p a r i n g Fig. 4a w i t h Fig. 4b it b e c o m e s o b v i o u s t h a t t h e d e p e n d e n c e o f the a p p e a r a n c e r a t e o n b l o o d flow is m o r e p r o n o u n c e d than of the disappearance rate. 3.3. DEPENDENCE OF SEROSAL APPEARANCE ON BLOOD FLOW T h e i n f l u e n c e o f b l o o d flow o n t h e s e r o s a l a p p e a r a n c e r a t e o f s e v e r a l s u b s t a n c e s has been investigated by Ocbsenfahrt 0973). A vascularly perfused jejunal loop from

D. WINNE

354 a

b

lOO ~ r c ~

i

2.0' llh O O

5ulfaethidote dog

1.5 / 1.0"

" O > ii 1; tY eJ

~

lib

dog

.5

percent ......... ,/ 0 50 100 Relative Venous Outflow Rate

0 ' ,

•

,

.

,

•

/

Flow Rate in sd" ~k~'6qulminMesent" Art.

c

, mllrr~.g .04-

R" .02- Oalactose 0{ + Phlorizine ~; .01rat 0

percent . . . . i . . . . T,/

rnl/min.~

o 5o lOO Relative F l o w Rate in Sup. Mesent. Art.

Venous Outflow Rate

FIG. 7. Examples for the dependence of the disappearance rate from intestinal lumen on blood flow rate. Panel a: disappearance rate and venous outflow rate related to initial values before constriction of mesenteric artery, data taken from Varr6 et al. (1965a); panel b: luminal disappearance characterized by first order rate constant (from semilogarithmic plot of fraction unabsorbed in lumen vs time), data taken from Crouthamel et al. (1975); panel c: disappearance rate standardized by luminal concentration (¢/CL), venous outflow rate and disappearance rate related to I g wet weight of intestinal tissue. Circles represent experiments with decreasing and squares with increasing flow rate. Venous outflow rate varied by raising or lowering systemic blood pressure. Data taken from Lichtenstein and Winne (1974).Panel d: flow rate in superior mesenteric artery related to initial value before constriction of the artery, unidirectional sodium fluxes calculated from systemic plasma concentration after intravenous and luminal administration (double labels), data taken from Love (1976). Bars indicate -+ standard error. Technical details and further experimental data showing similar relationships are given in Table 11. It

O a~

b

,' ml/min.g

mllmin.g ~ r ~

.15 '

.!o

i11

~05 el

Ethanol rat

i... ~

,T,..~,...~t

L-Phenylalanine rat

.05

~In~, "9/

"10

:,0

;

2

o ~ 2 Venous Outflow Rate

Venous Outflow Rate c . mllmin.g .10" w 3-0-Methylglucose ut rat

~ ..05"

d , 'mUmin .g .10.

Galactose rat

.05

eJ .~_

~,o

0

o

~

mUmin.g 2, /

Venous Outflow Rate

0

ml/m. 9

;

,

2

/

Venous Outflow Rate

FIG. 8. Examples for the dependence of the disappearance rate from intestinal lumen on decreasing and increasing flow rate. Venous outflow rate varied by raising or lowering systemic blood pressure. Disappearance rate standardized by luminal concentration (~/CL). Venous outflow rate and disappearance rate related to I g wet weight of intestinal tissue. Bars indicate _+standard error. Circles represent experiments with decreasing and squares with increasing flow rate, see also arrows. Data taken from Winne and Remischovsky (1971a), Winne (1973), Lichtenstein and Winne (1973, 1974). Technical details and further experimental data showing similar relationships are given in Table 13.

Jejunum

Jejunum

Jejunum

Jejunum

Jejunum

Dog

Dog

Dog

Rat

Cat

Cat

(To)

Jejunum

Jejunum

Rat

Dog

Small intest,

Jejunum

Rat

Dog

Jejunum

Rat

Magnetic flow meter

Venous .outflow Venous outflow Venous outflow Venous outflow

Magnetic flow meter Vascular perf. rate Venous outflow Venous outflow Venous outflow Venous outflow

Venous outflow

Constriction mesent, artery

System. blood pressure System. blood pressure System. blood pressure Constriction mesent, artery

Constriction mesent, artery Vascular perf. rate Constriction mesent, artery System. blood pressure Isoprenaline i.a. Constriction mesent, artery

Constriction mesent, artery

Blood flow rate Measured or given by Changed by

J,

~

~'

~

~'

~

1'

~

~

~'

~•

~

Sodium

Sorbose

Galactose + phlorizine Galactose + phlorizine Erythritol

Krypton

Krypton

Amidopyrine

Sulfaethidole Glucose Xylose Glucose

Glycine

Substance

140 mM

5%

100 ~M 2 mM I00 mM 2 mM 229/zM

746 ;tM

2.7 mgiml 25 mg/ml 25 mg/ml 5.4%

2.8%

Luminal concentr,

Single pass perfusion + tracer bolus injection

Single pass perfusion Single pass perfusion Single pass perfusion Repeated administr.

Repeated administr. Single administr. Repeated administr. Single pass perfusion Single pass perfusion Single pass perfusion

Single administr.

Mode of luminal administr,

c

v

r

175, 177 178, 193

300

337

172

172

133

133

O.W.

313 313 300

35, 36, 44

300

Remarks references

Technical details of the examples diagrammed in Fig. 7 and further experimental data showing similar relationships, v = vascularly perfused loop, r = determined rate constant = change of luminal amount with time, c = unidirectional fluxes calculated from systemic plasma concentration after intravenous and luminal administration (double labels), 1' = increased, ~ = decreased, O.W. = Ochsenfahrt and Winne unpublished.

(7d)

(7c)

Jejunum

Dog

(Ta)

Jejunum

Species

Fig.

Site of absorption

TABLE 11. Dependence of the Disappearance Rate from Intestinal Lumen on Blood How Rate

5¢D

C

e~

go

O

go ~r

=

m.

O

O

~r

,.s

Jejunum

Small intest. Small intest.

Dog

Rat

= decreased.

Cat

Small intest.

Dog

Species

Site of absorption

Magnetic flow meter

100% 100%

Hydrogen Carbondioxide

~ ~

Constriction mesent, artery Partially obstruction portal vein

1.24 mg/ml 145 m equ/l tracer 5.4%

Sodium Sodium-22 Glucose

Glucose

~,

72%

Compression of aorta

Carbondioxide

~

Substance

Luminal concentr, or dose

Constriction mesent, artery

Blood flow rate Measured by Changed by

Repeated administr, Single administr,

Repeated administr,

Repeated administr,

Mode of luminal administr,

Disappear. rate Disappear. rate

Decrease of luminal concentr. Disappear. rate

Measured quantity

Slower

Effect

TABLE 12. Miscellaneous Data on the Influence of Intestinal Blood Flow on The Disappearance From the Intestinal Lumen

188

188

2O5 205 173

2O5

225

Remarks references

z

O~

Influence of blood flow on intestinal absorption of drugs and nutrients

357

ITABLE 13. Dependence of the Disappearance Rate From the Lumen of Rat Jejunum on Decreasing and

htcreasing Venous Outflow Rate

Fig. (Sa)

(8b)

(8c)

(8d)

Blood flow rate changed by System. blood pressure System. blood pressure System. blood pressure System. blood pressure System. blood pressure System. blood pressure System. blood pressure System. blood pressure Inflow pressure Inflow pressure

Substance

Luminal concentr,

Ethanol

34.3/tM

Methanol

37.6/, M

Ethylene glycol Antipyrine

274 I*M 13.5/,M

Amidopyrine

746/,M

Mode of luminal administr,

Remarks references

Antipyrine

329/zM

L-phenylalanine Antipyrine

33.3 mM

Single pass perfusion Single pass perfusion Single pass perfusion Single pass perfusion Single pass perfusion Single pass perfusion Single pass perfusion Recircui,

14.2/,M

Recircul.

v

215

6.3 ~M

Recircul.

v

215

Aniline

Salicylic acid

12/,M

System. blood pressure System. blood pressure System. blood pressure System. blood pressure System. blood pressure System. blood pressure Inflow pressure Inflow pressure

L-pbenylalanine Benzoic acid Benzoic acid Salicylic acid 3-O-methylglucose L-phenylalanine L-phenylalanine 3-O-methylglucose

31.1/zM 33.3 mM 21.5/*M

System. blood pressure System. blood pressure System. blood pressure System. blood pressure System. blood pressure System. blood pressure

3-O-methylglucose ~phenylalanine Urea

3-O-methylglucose"

27.3 mM

System. blood pressure System. blood pressure

Galactose

100/,M 100 mM 32.3/zM

Glycerol Ribitoi

Salicylic acid

336 336 337 O.W. a

O.W.

a

269

a

269 329

21.5 zM

Single pass perfusion Single pass perfusion Single pass perfusion Single pass peffusion Recircul.

30.9 ~td

Recircui.

91.8 ,,M

Recircul.

v

215

12.3 ~M

Recircul.

v

215

37.8/zM 38 mM 34.5/,M

Single pass perfusion Single pass perfusion Single pass perfusion Single pass perfus'ion Single pass perfusion Recircul.

21.5 *M 12.8 ,M

11.6 ~,M 20 g,M 189/,M

Single pass perfusion Single pass perfusion

329 329 O.W. a

O.W.

a

269 171 329

171 171 329 336 337 337 171 172 172 O.W.

Technical details of the examples diagrammed in Fig. 8 and further experimental data showing similar relationships. All data obtained in rat jejunum, blood flow rate measured by venous outflow, a -- acidic luminal solution (pH 2.2 or 3), v = vascularly perfused loop, O.W. = Ochsenfahrt and Winne unpublished.

the rat is s u s p e n d e d i n a s e r o s a l b a t h a n d a b u f f e r e d s o l u t i o n w i t h the s u b s t a n c e o f i n t e r e s t is r e c i r c u l a t e d t h r o u g h t h e l u m e n b y a b u b b l e lift. I n this p r e p a r a t i o n the d i s a p p e a r a n c e rate f r o m t h e i n t e s t i n a l l u m e n a n d the a p p e a r a n c e r a t e s i n the i n t e s t i n a l v e n o u s b l o o d a n d in t h e s e r o s a l b a t h c a n b e m e a s u r e d s i m u l t a n e o u s l y c h a n g i n g the b l o o d flow rate f r o m z e r o to high v a l u e s a n d vice v e r s a . F i g u r e s 9a a n d b s h o w the

D. WINNE

358

b

II 'mllmin. g

~~

C

0

nt/aptyrine

.1.

...o

O' ?"

05

~"'~,i ~

•

0

,

-1 . i / ~ , l ~ r i n e ,..i-~

ml,,min.~" - !

I

2

o.

""

~.lm.,;g

0

1

.

,~ 2

Venous Outflow Rate

Venous Outflow Rate

c :[ mllmin.g i

d ~Iml/min'g

1 ']~ ": t~

mll min.g

rat

~ -[: L"~

//

~z'..-.,.,~,-,h.-, _.lj ' ,',t,' ,1 0 I 2rrdlmin-g 0 I Venous Outflow Rate Venous Outflow Rate

O~

•

F[o. 9. Examples for the dependence of the disappearance rate from intestinal lumen and the appearance rates in intestinal venous blood and serosal bath on decreasing and increasing flow rate (lowering [a and c] or raising arterial pressure [b and d]). Vascularly peffused rat jejunal loop. Absorption rates standardized by luminal concentration (O/CL). Venous outflow rate and absorption rates related to 1 g wet weight of intestinal tissue. Bars indicate -+ standard error. Dotted lines: extrapolation of appearance rate in intestinal venous blood to zero flow rate. Squares: disappearance rate, circles: appearance rate in intestinal blood, triangles: appearance rate in serosal bath. Arrows indicate direction of blood flow change. Data taken from Ochsenfahrt (1973).

dependence of the antipyrine absorption rates on venous outflow rate changed in separate experiments from high values to zero or from zero to high values. With decreasing blood flow rate the appearance rate in the blood and the disappearance rate from the lumen decreases, first slowly then faster, while the appearance rate in the serosal bath increases. At zero blood flow rate the disappearance rate from the lumen is small and corresponds to the appearance rate in the serosal bath: in vitro conditions. This example demonstrates clearly that in the presence of an intact blood drainage the absorption of highly absorbable drugs is three to four times larger than under in vitro conditions. The subepithelial tissue represents a considerable resistance causing low permeation rates in vitro. It should be noticed that at normal (1 ml/min g) or high (2 ml/min g) blood flow rates the appearance of antipyrine in the serosal bath does not cease completely. In spite of a good blood drainage of the intestinal wall a small amount of antipyrine reaches the serosal surface and enters the bath. Also in the vascularly perfused rat jejunum a different relationship between the absorption rates of L-phenylalanine and blood flow in experiments with decreasing and increasing flow rate has been observed (Figs. 9c and d). 3.4. DEPENDENCE OF LUMINAL APPEARANCE ON BLOOD FLOW Only four investigations concerning the influence of blood flow on the blood-tolumen permeation of substances are known to the author (Table 14). The appearance rate of tritiated water in the intestinal lumen increases or decreases with increasing or decreasing intestinal blood flow. The compression of aorta reduces the secretion of potassium and the change of pH in acid solutions in dog small intestine.

Jejunum

Jejunum

Duodenum

Jejunum

Species

Rat

Rat

Dog

Dog

Venous outflow

Compression of aorta

System. blood pressure Compression of aorta

System. blood pressure

Blood flow rate Measured by Changed by

= increased, ~ = decreased.

Site of .absorption

~

~

~'

~

Potassium

Trifiated water Potassium

Tritiated water

Substance

Repeated administr.

Single pass perfusion Repeated administr,

Single pass perfusion

Mode of luminal fluid administr,

Increase of luminal K retarded ~

~

~

Effect on luminal appearance

T^BLE 14 Dependence of the Appearance Rate in the Intestinal Lumen on Blood Flow rate

205

204

curves as in Fig. 6a 327 222

Remarks references

e~

e~

O

go ~r

O

O

[

a"

o

0

D. WINNE

360

3.5. DEPENDENCE OF FLUID ABSORPTION ON BLOOD FLOW The dependence of intestinal fluid absorption on blood flow is complicated, since several factors interact: arterial and venous pressure (Lee and Duncan, 1968; Lee, 1973), luminal hydrostatic pressure (Lee, 1965), osmotic pressure (Lee, 1973, 1974), motility (Lee, 1965), contractility of the lymph vessels (Lee, 1963, 1965), and motility of the villi (Lee, 1971). The data of Lee and Duncan (1968) obtained in the vascularly perfused rat jejunum in vitro demonstrate the influence of the arterial and venous pressure on arterial inflow rate and fluid absorption (Fig. 10). In these experiments the appearance rate of fluid in the venous blood has been determined by the difference of the venous outflow and arterial inflow rate. The sum of the appearance rate and the lymph flow rate is the disappearance rate from the lumen as verified by separate experiments. In Fig. 10 the disappearance and appearance rates at 70 and 100 mm Hg arterial pressure are plotted vs the arterial inflow rate. The lymph flow rate is represented by the distance of corresponding points on the two curves. On raising the venous pressure at constant arterial pressure the arterial inflow rate first increases then decreases, especially at high venous pressure. The fluid absorption (disappearance as well as appearance rate) increases and decreases almost in parallel. The complicated relationships are seen if the influence of arterial pressure at constant venous pressure is examined--compare corresponding points of the curves for 70 and 100 mm Hg arterial pressure. On raising the arterial pressure at zero venous pressure the arterial inflow rate and the fluid absorption increases. At 5 mm Hg venous pressure the arterial inflow rate increases, but the fluid absorption remains unchanged. At 10 mm Hg venous pressure the increase of the arterial pressure slightly increases the arterial rate and considerably reduces the fluid absorption. On raising the arterial pressure at 15 mm Hg venous pressure the fluid absorption is reduced without change in the arterial inflow rate. The lymph flow rate increases with increasing venous pressure as shown by the increasing vertical distance between the curves for the disappearance and appearance rates. At low venous pressure, 10-20 per cent of the absorbed fluid appears in the lymph. The residual fraction is drained by blood. At the highest venous pressure used, the total amount of absorbed fluid appears in the lymph augmented by the fluid transferred from blood to lymph. Therefore, negative appearance rates have been measured. In the restrained conscious rat, the ingestion of 5 ml water and isotonic saline increases the flow in a mesenteric lymphatic fistula by 0.7 and 0.55 ml, respectively

d/h.cm

Arterial Pressure 70ram Hg lOOmm Hg

0 U C m

~.

;;\

.,°

ew 200

x2

~so

• iO0"

) m o u i-

.

~ o' 8: ~-~

•

v' U'r"

, ~ , ~, ~.~. 0 Arterial Inflow Rate

~." mllh.cm

FIG. 10. The dependence of fluid absorption on blood flow. Vascularly perfused jejunal loop of rat. Disappearance rate from intestinal lumen (squares), appearance rate in intestinal venous blood (circles), and arterial inflow rate related to I cm intestinal length. Venous pressure (figures in diagram) varied. Appearance rate in lymph = difference between disappearance rate and appearance rate in blood. Two experimental series with arterial pressure adjusted to 70 and 100 mm Hg. Data taken from Lee and Duncan (1968).

Influence of blood flow on intestinal absorption of drugs and nutrients

361

(Barrowman and Roberts, 1967). The excess lymph represents 14 and ll per cent of the ingested water volume. In vitro, without blood drainage, the main fraction of the absorbed fluid appears in the lymph and only a small fraction in the venous vessels (Lee, 1961, 1963, 1969). Further data (Table 15) show also that--in most cases--a reduction of blood flow decreases the positive (disappearance rate) or negative (luminal appearance rate, secretion) water net flux. 3.6. INFLUENCE OF VASOACTIVEDRUGS ON INTESTINAL ABSORPTION The data listed in Tables 16 and 17 concern the influences of--mainly vasoactive-drugs on intestinal absorption. The intestinal blood flow rate was not measured in all investigations. Generally, the absorption increases or decreases in parallel to the intestinal blood flow change induced by the administered drug. Norepinephrine, pilocarpine, 5-hydroxytryptamine, pituitary extract, and vasopressin reduce the intestinal blood flow rate and the absorption rate, while isoprenaline, secretin, cholecystokinin, theophylline, caffeine, and PGE~ raise both rates. The reduced intestinal blood flow after the administration of pilocarpine is due to the increased motility, particularly to the tonic contractions (Pytkowski and Lewartowski, 1972; Pytkowski and Michalowski, 1977). Epinephrine decreases the disappearance rate of glucose irrespective of the--lowered or raisedmblood flow rate. Histamine increases the intestinal blood flow and the appearance rate of tritiated water in the jejunal blood of rats, but decreases the disappearance rate of glucose from dog jejunum. The jejunal and ileal secretion of fluid is enhanced. Acetylcholine increases the intestinal blood flow rate, while it decreases the disappearance rate of glucose from dog jejunum. Indomethacin reduces the blood flow rate and the luminal appearance of tritiated water, but increases its appearance in the intestinal blood. Glucagon infused intraarterially increases the unidirectional fluxes of sodium and water and the ileal blood flow in dogs, while the administration of glucagon into an adjacent non-perfused segment has the opposite effect. A change of the absorption rate by vasoactive drugs can occur without changing the blood flow rate. The intravenous infusion of 0.59 ng/kg min angiotensin increases the fluid absorption from rat jejunum, while at an infusion rate of 590 ng/kg min the fluid absorption is lowered (Bolton et al., 1975a, b). In these two experiments the intestinal blood flow rate remained unchanged. 3.7. INTESTINAL LYMPH DRAINAGE OF XENOBIOTICS The lymph vessels represent a second pathway for the drainage of substances absorbed from the gastrointestinal lumen. Here, mainly the lymph drainage of xenobiotics shall be reviewed. It is necessary to have a brief look at the methods used to investigate the intestinal lymph drainage of substances administered orally or into the stomach and intestine. In the rat the major intestinal lymphatic in the mesentery (Bollman et al., 1948; Peters and MacMahon, 1970; Warshaw, 1972) or the abdominal thoracic duct (Bollman et al., 1948; Gallo-Torres and Miller, 1969) is cannulated. The lymph can be collected for several days. In the experiments with cats listed in Table 18 the intestinal lymph vessel and in the experiment with dogs the thoracic duct above the cisterna chyli were cannulated. Usually only the appearance of the administered substance in the intestinal or thoracic duct lymph is measured. Since intravenously administered substances appear also in the intestinal lymph (Benson et al., 1956; De Marco and Levine, 1969; Forth et al., 1969; Oliver et al., 1971; Seifert et al., 1975; Sieber et al., 1974), it must be taken into account that t h e amount recovered in the lymph after gastrointestinal administration originates only partly from the intestinal lumen. In four investigations listed in Table 18 the appearance of the absorbed substance in the portal venous blood was determined simultaneously. The data listed in Tables 18 and 19 show that for hydrophilic substances the fraction drained by lymph is small. With increasing lipid solubility this fraction

Jejunum

Jejunum

Jejunum

Small intest,

Species

Rat

Rat

Dog

Dog

Venous outflow

Arterial inflow rate Venous outflow ~

System. blood pressure

Compression of aorta Pituitary extract

~

Venous pressure

Blood flow rate Measured or given by Changed by

Tap water

Disapp.

Disapp. Repeated administr. Repeated admirdstr.

Isotonic

~,

J,

appear. lymph flow Disapp. =

~sapp.

Effect on water net flux

Disapp. Luminal appear.

Single pass perfusion

Repeated administr.

Mode of luminal administr.

Hypotonic Hypertonic

Isotonic

Isotonic

Luminal osmolarity

v -- vascularly perfused loop, T = increased, ~, = decreased, = unchanged.

Site of absorption

TABLE 15. Dependence of Intestinal Fluid Absorption on Blood Flow Rate

V

243

205

321 321

321

Fig. 10 164

See

Remarks references

z ~n

bJ

i.a.

2.5-70 /~g/min

1'

~'

i.a.

i.v. s.c. i.v.

I mg/kg 0.1, I mg/kg 50/z g/rain Venous outflow

Venous outflow Venous outflow

Venous outflow Venous outflow

Magnetic flow meter

Venous outflow

Venous outflow Venous outflow Venous outflow Venous outflow Magnetic flow meter

Venous outflow

Rat

Rat

Jejunum Ileum Small intest. Jejunum

Jejunum

Dog DOg

Colon

Jejunum

Jejunum

Ileum

Jejunum

Jejunum

Jejunum

Jejunum

Jejunum

Jejunum Jejunum

Jejunum

Site of absorption

Dog

Rat

Rat

Dog

Dog

Dog

Dog

Cat

Cat

Dog

Rat

Rat

Species

Tritiated water

Glucose

Fluid

D,L-serine D,L-phenylalanine L-serine L-phenylalanine Tritiated water Tritiated water Chloride fluid Glucose

Carbon dioxide

Glucose

Krypton

Krypton

Tritiated water Tritiated water Glucose

Substance

Repeated administr. Single pass perfusion

Single pass perfusion Single pass perfusion Single administr. Repeated administr.

Repeated administr.

Repeated administr.

Single pass perfusion Repeated administr, Single administr,

Single pass perfusion i.p. Repeated administr. Recircul.

Mode of administr, ~

~

1'

1'

1'

=

J, ~

App.

Dis. [ 1`

Secretion

Dis. 1' Dis. 1' Dis. = , ~

App.

App.

App. App.

Decrease of luminal concentr. flatter App. ~ App. ~,

Dis.

Dis.

App.

1`

Lum. app. ~ Dis. ~, ~

App.

Effect on absorption

320

173

165

241 241 304

320

320

240

239

225

304

See Figs. 2d, 3a, 5. 16 133

222 304

320

Remarks references

= decreased, T = increased, = no change, app. = appearance rate in intestinal venous blood, dis. = disappearance rate from intestinal lumen, lum. app. = appearance rate in intestinal lumen, ( ~ )* = reduction of the blood flow increase produced by carbon dioxide.

= , 1'

Histamine

i.a.

s.c.

1'

=

~

~,

( ~ )*

1'

1'

I'

~, 1'

~

Blood flow change Measured by

0.1-0.2 mg/kg 3.33-13.3 ~g/min 2 mg/hr

i.v.

150/zg

Atropine

i.v.

15/tg

Neostigmine

s.c.

i.a.

Methacholine

20-50/zg

i.a.

5-10 ~g/min

Pilocarpine

i.a.

i.a.

i.v. i.a.

20 ~g/min kg 0.66--6.60 /~g/min 2-10 p~g/min

2.33-266.6 p.g/min 2.5--3.5 mg

i.v.

6 ttg/min

Dose

~cetylcholine

|soprenaline

Epinephrine

Norepinephrine

Drug

TABLE 16. Effect of Vasoactive Drugs on Intestinal Absorption I

.~° '~ = 5".

~"

~" =

~-

-~'

~"

o

~" ~.

o

•m

0.5 mg

0.5, 6.5 g/ml

I p.g/ml

Caffeine

PGE~

lndometacin

Angiotensin

Theophylline

5/zg/min 2.5 mg 5 lZg,/min 2.5 mg 8 ttg/min

2.5-10.5 U/kg h 2.5-10.5 U/kg h 0.5-1.0 ml 0.25, 1 0.1-1 U.I. 0.02 U/min

Dose

20/zg/ kg min 0.59 ng/ kg min 590 ng/ kg rain 0.5 mg

5-hydroxytryptamine

Vasopressin

Cholecystokinin Pituitary extract

Secretin

Drugs

i.1.

i.l.

i.l.

~

1'

1'

~'

=

i.v.

i.l.

=

~

i.v.

i.v.

i.v. i.l. i.v.

i.i.

i.v.

Venous outflow

Venous outflow Venous outflow

Cardiac output + Fractional blood flow Venous outflow

Venous outflow

Venous outflow

Rat

Rat

Rat

Rat

Rat

Rat

Rat

Rat

Rat

Rat

~

Dog

i.v.

J,

s.c.

Cat

Cat

Rat

1'

i.a

Venous outflow Venous outflow Venous outflow

Species

i.v. s.c.

1"

i.a

Blood flow change Measured by

Jejunum

Jejunum

Jejunum

J

Jejunum ~

Jejunum

Jejunum

Jejunum

Jejunum

Colon

Jejunum

Small intestine Small intestine

Jejunum

Jejunum

Site of absorption

Trit/ated water

['Tritiated ! water, urea antipyrine [salicylic L acid TrRiated water

Tritiated water Fluid

Tritiated water Tritiated water Tritiated water Tritiated water

Glucose

Water

Krypton

Krypton

Substance

Single pass perfusion i.v. Single pass peffusion i.v.

Repeated administr.

Single pass perfusion Single administr. Single administr. Single pass perfusion Single administr. Femoral vein

r

t , 1'

lum. app. App. 1' lum. app.

1'

1'

App. = ,

App.

Dis.

10

10

I1

19, 20

19, 20 1'

Dis.

320

166

222

~

Lum. app.

App.

App.

App. sy.

275

~

App. sy.

173

243

See Fig. 5 12 12

320

~

~

1'

1'

Remarks references

App.

Dis.

Dis.

App.

Recircul. Repeated administr. Repeated administr.

App.

Effect on absorption

Recircul.

Mode of administr,

TABLE 17. Effect of Vasoactive Drugs on Intestinal Absorption H

.~ .~ z m

i.a.

i.a. indirectly*

0.05-0.5 p.g/kg min

0.05-0.5 /~g/kg rain

~

1"

Clearance tritiated water Clearance tritiated water Dog

Dog Ileum

Ileum Sodium [ water J

Sodium ~ water J Single pass perfusion

Single pass perfusion ~ unidir. ~ [ net flux ,[

[ unidir. 1' [ n e t flux = 186

186

= decreased, T = increased, = no change, app. = appearance rate in intestinal venous blood, dis. = disappearance rate from intestinal lumen, lure. app. = appearance rate in intestinal lumen, app. sy. = deconvolution of the concentration curves in the systemic blood after luminal and intravenous administration, i.l. = into the intestinal lumen, r = determined: rate constant of appearance rate in intestinal venous blood, *into the artery of a non-perfused segment.

Glucagon

5. o

o-

es

O

O"

E

O

O

O"

o

¢) ¢1

5.2

1.8 1.1 2.62

90 min

42 min 42 min 42 min

41

40 mg in 2 ml water duodenum +A

p -aminosalicylic acid

Rat

Disappearance from intestinal lumen

81 81 81

1.8 4.7

60 min

61

6.8 ttCffmin, 1 ml/min Krebs bicarbonate buffer, single pass perfusion, duodenum to ileum

HTO

Rat

Disappearance from solution perfused through lumen

0.7

18 min

77

Duodenum

Thorac. Mesent. Thorac.

Mesent.

1.2 0.6 1.8

1.3

0.8

20 min

84

Appearance in the collected portal venous blood

0.2 ml + 0.5 ml infusion fluid, stomach

I~O

Rat

Mesent.

I hr

0.11 0.39

0.02 0.01 0.006 0.015

0.02 0.014 0.006 0

65.8 83.2

Mesent.

Mesent.

Thorac.

1.5 0.7 2.3

0.035 0.095 0.014 0.057

Percentage recovered of amount Administered Absorbed

Appearance in portal venous blood from arterio-venous concentration difference and portal flow rate (bubble flow meter)

1 hr

3hr

Site of Volume . Lymph ml collection

1.28/zmol in 4 ml saline (2.5 mmol/l tris), jejunum

56.5 10.5 42.5 26.5

72 68 45 0

Appearance in portal venous blood from arterio-venous concentration difference and portal flow rate (bubble flow meter)

Appearance in portal venous blood from arterio-venous concentration difference and portal flow rate (ultrasonic flow meter)

lOOnmoi in 2ml saline, jejunum

lOOg) in 400mi I00 g l, saline 100 g [ duodenum 50gJ

Absorption measured by

Lymph Sampling period

Bumadizone phenylbutazone

Ouabain Digoxin Peruvosid

Digitoxin

Galactose Fructose Inulin

Glucose

Substance

Percentage absorbed

Cat

Cat

Dog

Species

Mode and site of administration

TABLE 18. Appearance of Xenobiotics in Mesenteric and Thoracic Duct Lymph L

M 43

211

C 8

M 272 "

M 68, 69

273

Remarks references

Z

Benzene Benzoic acid Aniline p-aminobenzoic acid Salicylic acid Anthracene Phenanthrene Hexanol Octadecanol Hexylamine Octadecylamine Hexanoic acid Octadecanoic acid Cholesterol Testosterone Estradiol Digoxin Antipyrine Isoniazid Caffeine p,p'DDT

0.72/~ mol/kg I0/~mol/kg 5/z mol/kg 0.04/~ mol/kg 150/~ mol/kg 95/~ moi/kg 51 ~ moi/kg 1.8/~ mol/kg in 5 mi/kg water or 10-50% ethanol, duodenum

5/~mol/kg

20 mg in 1 ml water +A 20 mg + 5 mg EDTA in l ml water

Disappearance from intestinal lumen

18.5 28.3 27.6 24 hr

2 hr 2 hr 2 hr 67.2

2.4 4.1 2.5 Thorac.

Thorac.

0.05 0.15 0.12 0.2 1.4 2.3 1.9 4.0 2. I 1.8 8.5 56.6 3.7 7.6 3.3 52.5 101.3 1.2 1.2 1.7 3.4 6.6 6.1 19.9

0.28 0.54 0.43

B

M 32, 282

A = 4 m l tripalmitin solution (=60rag) intragastrically 2 h r before; M =including metabolites; C = infusion of saline (2.3 ml/h) into stomach; B = intraduodenal infusion of 0.9 per cent NaCI + 0.04 per cent KCI, 0.094 mi/min.

Rat

Tetracycline

CI.

~° O

~o

5'

o

o

-a

O"

¢0

-h

Quinestrol

Ethinylestradiol

Cis-dimethylaminostilbene Dimethylaminobibenzyl 14.9/~g in 0.5 ml water, stomach 18.3 tzg in 0.5 mi sesame oil, stomach 17.2 p.g in 0.5 ml water, stomach 18.8 t~g in 0.5 ml sesame oil, stomach 23.5 p.g in 0.5 ml

5 mg/kg 25 mg/kg in 0.5 ml sesame oil, stomach 5 mg/kg in 0.5 ml sesame oil, stomach 5 mg/kg in 0.5 ml sesame oil, stomach

Trans-dimethyl-

Rat

Rat

4hr

0.8 mg in 2 ml trioleine emulsion 2 mg in 5 ml trioleine emulsion small intestine

Sudan blue

Rat

24 hr

24hr

3 hr

30 mg/hr, 3 ml/hr 60 mg/hr, 3 ml/hr 120 mg/hr, 3 ml/hr infusion, duodenum

Bromsulfothaleine

Rat

aminostilbene

1 hr

0.2 ml + 0.5 ml 5% glucose, stomach 0.2 ml + 0.5 ml 0.9% saline, stomach 0.2 ml + 0.5 ml water stomach

Mode and site of administration

D20

Substance

Rat

Species

Lymph sampling period

294

207

0.030 0.012 0.012

1.7

Mesent.

Mesent.

0.38 1.47 7.53 15.7

23.7 23.2 20.6

0.59

23.4 20.0

10.6 71

5.2 7.3 4.9

Thorac.

Thorac.

46

102 51

2.1

M 82, 83

M 141

C

0.33

0.47

Mesent.

1.50

0.83 0.86

Remarks reference

2.14

Percentage recovered of amount administered A 8 B

Volume . ml

Site of lymph collection

TABLE 19. Appearance of Xenobiotics in Mesenteric and Thoracic Duct Lymph II

z

oo

7,12-dimethylbenzanthracene

Dibenz(a-h) anthracene

DDT

p,p'-DDT o,p-DDT p,p'-DDD o,p-DDD DDE DDA 2,4-D

Rat

Rat

Rat

Rat

10/~mol/kg in 0.5 ml/kg dilute ethanol solution + 0.5 ml/kg for flushing

100 nmol in sunflower seed oil, stomach

5 ~.g-2 mg in 0.5 ml sesame oil, stomach

20 mg in 1 ml sesame oil, stomach

10 mg in I ml sesame oil, stomach

24 hr

4 hr 12 hr 3d >3d

24 hr

24 hr

12 hr

Thorac.

Thorac.

Thorac.

Thorac.

Thorac.

15.6 24.4 15.9 12.2 33.3 6.8 3.5

55 61.1 63.3 > 70

5

40

10-20

M, E 280

M 236

M 39

127

D 244

A = infusion of 5 per cent glucose (2.3 ml/hr) into stomach; B = infusion of 0.9 per cent saline (2.3 ml/hr) into stomach; C = infusion of water (2.3 ml/hr) into stomach; D = infusion of saline (3 ml/hr) into duodenum; E = infusion of 0.9 per cent NaCI + 0.04 per cent KCI (0.094 ml/min) into duodenum; M=including metabolites; trioleine emulsion=0.04ml trioleine+2mg/ml polysorbate 80; DDE=2,2-bis-(p-chlorophenyl)-l,l-dichloroethylene; DDA = bis-(p-chlorophenyl)-acetic acid; 2,4-D = 2,4-dichlorophenoxyacetic acid.

benzo(a)pyrene

Rat

sesame oil + 25% glyceromonooleate stomach

~D

¢D

e~

to

e-

o

Ig ~e

-t

D.

O

0.

o

370

D. WINNE

increases. The chylomicrons contain, mainly in the core, up to 90 and more per cent of the transported lipophilic xenobiotics, while substances poorly absorbed by lymph are distributed predominantly in the aqueous phase of the lymph (Cohn and Sieber, 1970; Janss and Moon, 1970; Pocock and Vost, 1974; Sieber et al., 1974; Kamp and Neumann, 1975; Sieber, 1976). The concentration of the absorbed substances in the lymph lies below (Forth et al., 1969; Oliver et al., 1971; Seebald and Forth, 1977), about or above the plasma level (De Marco and Levine, 1969; Sieber et al., 1974; Sieber, 1976). A high initial lymph-plasma concentration ratio has been observed, especially for lipophylic substances e.g. 80 for 2,2-bis(p-chlorophenyl)-l,l-dichloroethylene and p,p'-DDT (Sieber, 1976). Tripalmitin in the diet doubles the lymph flow and simultaneously the fraction of p-aminosalicylic acid and tetracycline transported by the lymph (De Marco and Levine, 1969). The vehicle of administration plays an important role for lipophilic xenobiotics. The fraction of quinestrol recovered in the lymph collected 24 hr after peroral administration in aqueous solution amounts to 1.5 per cent. Administration in sesame oil raises this fraction to 7.5 per cent and, in sesame oil with 25 per cent glycerylmono-oleate, to 16 per cent (Giannina et al., 1966, 1967). From p,p'-DDT administered in ethanol 20 per cent is recovered in the 24 h-lymph but 33 per cent, if the substance is given in olive oil (Sieber et al., 1974). Similarly the lymph drainage of compounds structurally-related to DDT is doubled, if they are given in corn oil instead of in ethanol (Sieber, 1976). On the other hand, the administration of digitoxin in an emulsion of 25 per cent saline and 75 per cent olive oil did not increase the appearance rate in the portal venous blood and the intestihal lymph (Forth et al., 1969). The fraction of p,p'-DDT in lymph is reduced to 9 per cent in bile cannulated rats (Sieber et al., 1974). Sudan blue does not appear in the lymph of bile fistulated rats, while about 2 per cent of the administered dose is recovered within 4 hr in the lymph of intact rats (Noguchi et al., 1975). These observations indicate that fat absorption must be undisturbed for the lymph drainage of lipophilic xenobiotics. While highly lipophilic xenobiotics seem to be absorbed on the lymphatic pathway, the hydrophilic substances appear almost exclusively in the portal venous blood. A substance distributed in the intestinal tissue represents a pool which is filled up from the intestinal lumen and/or the arterial blood depending on the concentration gradient and is drained by the venous blood and the lymph according to their flow rates (Wilson, 1962, p. 9; Parsons, 1975b). Since the lymph flow rate amounts to 1/200 to 1[700 of the blood flow rate (Benson et al., 1956; Wilson, 1962, p. 9; Forth et al., 1969, 1970), only a small fraction of a hydrophilic xenobiotic is carried away on the lymphatic pathway. 3.8. INFLUENCE OF HEMORRHAGIC SHOCK ON INTESTINALABSORPTION

Some examples are given to illustrate the different effects of hemorrhage on intestinal absorption. The absorption of xylose is reduced during hemorrhagic shock (Ambromovage et al., 1971), the absorption of chloride and glucose is reduced (Lluch Trull, 1954; Hankes et al., 1969) or unchanged (Van Liere et al., 1938, 1947a; Fromm, 1973) and of sodium is reduced (Hankes et at., 1969), unchanged (Hankes et al., 1969) or increased (Mailman and Ingraham, 1971; Fromm, 1973). Magnesium (Van Liere et al., 1947b) and sulfate (Van Liere et al., 1947a and b) are absorbed at the same rate before and after hemorrhage. The increased absorption of inulin in hemorrhagic shock (Ambromovage et al., 1971) indicates a higher permeability of the intestinal epithelium to passively transported substances of higher molecular weight. The fluid absorption is reduced (Van Liere et al., 1938; Hankes et al., 1969; Cook et al., 1971), unchanged (Van Liere et al., 1938, 1947a; Mailman et al., 1967; Hankes et ai., 1969) or increased (Van Liere et al., 1938; Mailman and Ingraham, 1971; Fromm, 1973); the composition of the administered fluid apparently plays a role. The secretion of fluid into the intestinal lumen filled with MgSO4-solution is increased (Mailman et al., 1967). The partly contradictory results may be due to the different degree and state of the hemorrhagic shock induced.

Influence of blood flow on intestinal absorption of drugs and nutrients

371

3.9. INFLUENCE OF ISCHAEMIA ON INTESTINAL ABSORPTION According to the experiments of Robinson and co-workers (1964, 1965), Lluch Trull (1954), and SYlv6n (1970, 1971) the critical duration of an intestinal ischaemia seems to be 5-10 min (Table 20). During and after an ischaemia of 5 min or less, absorption is not impaired. A longer lasting ischaemia reduces the absorption capacity of the intestine for actively transported substances as shown by in vivo and in vitro absorption studies during and after the ischaemic period (Table 20). The transfer of passively transported substances during the ischaemia is reduced (lack of drainage), but after the ischaemic period the transfer is unchanged (urea, sorbose) or increased (iodide, polyvinylpyrrolidone, inulin, vitamin BI2, creatinine). These observations indicate that an ischaemia can increase the permeability of the epithelium for passively transported substances. But this cannot be detected before the drainage of the tissue is restored. The progressive damage of active transport mechanisms and not of passive ones by oxygen deficiency during the ischaemic period is demonstrated by the following observation (Ochsenfahrt, 1973). During an ischaemia of 90 rain duration, the disappearance rate of L-phenylalanine falls after 30 min to 1/5 of the initial value and the rate of 3-O-methylglucose decreases continuously to the same level. The disappearance rate of antipyrine and salicylic acid is lower during the ischaemic period (lack of drainage), but the rate does not change with time in contrast to the disappearance rate of L-phenylalanine and 3-O-methylglucose. The deleterious effects of an ischaemia can be alleviated by an intraluminal perfusion of the loop with mannitol, Ringer-lactate, Krebs buffer with and without glucose (Mirkovitch et al., 1975) or by placing glucose containing buffer into the loop during ischaemia (Robinson et al., 1966; Robinson and Mirkovitch, 1972). Partial recovery of intestinal functions can be observed as early as 24 hr after the ischaemia (Robinson et al., 1975). Full recovery is reached after 2 (Robinson et al., 1966) or 7 days (Robinson et al., 1965, 1974, 1976; Robinson, 1966). If the loop has been filled with glucose containing buffer during the period of ischaemia, the structural and functional recovery is complete one day later (Robinson and Mirkovitch, 1972; Robinson et al., 1973). The response of the ileal mucosa to ischaemia above and below a mechanical obstruction, and the recovery, follow the same pattern as when there is no occlusion superimposed (Mirkovitch et al., 1976). The literature pertaining to experimental malabsorption syndromes induced by several methods in laboratory animals has been reviewed and discussed by Robinson (1972).

4. T H E O R E T I C A L INTERPRETATION A series of models have been used or proposed to interpret quantitatively experimental data concerning the influence of blood flow on intestinal absorption. These models have been reviewed recently by Winne (1978). Here, only one model is described in detail to elucidate the theoretical background.

4.1. THE MODEL The natural situation in the intestinal wall is simplified (Fig. 11). A barrier separates the intestinal lumen from the interstitial space. This--first--barrier summarizes all the transport resistances between the well-mixed bulk phase of the intestinal lumen and the interstitial space (mainly the luminal unstirred layer and the intestinal epithelium). The substances in the interstitial space are drained by capillaries (basal membrane and capillary wall--second barrier) or penetrate through deeper layers of the intestinal wall 0amina propria, muscle layers, and serosal epithelium = third barrier) into a serosal bath. The second and third barrier represent parallel resistances while they are arranged in series relative to the first barrier.

Uptake of L-isoleucine into tissue of rat jejunum Uptake of L-phenylalanine into tissue of dog jejunum Disappearance of glucose from rat small intestine

* = net flux changed from 'absorption' to 'secretion'. Numbers refer to references at end.

After Ischaemia of 10 Min Duration or More in vitro Uptake of L-phenylalanine, L-isoleucine into tissue of rat small intestine Uptake of L-phenylalanine into tissue of dog jejunum Uptake of L-phenylalanine, B-methylglucosid into mucosa of dog small intestine into mucosa of dog colon Net transfer of sodium through mucosa of dog colon Transfer of glucose through guinea pig small intestine Transfer of sorbose through guinea pig small intestine Transfer of iodide through rat small intestine in vivo Uptake of iron into tissue of rat small intestine Disappearance of glucose from rat small intestine Disappearance of glucose from dog small intestine Disappearance of olive oil from rat small and large intestine Net flux of fluid, sodium, chloride in dog small intestine Urinary excretion of jejunally administered vitamin B~z (rat) Appearance of intravenously administered polyvinylpyrrolidone, inulin, vitamin Bn, creatinin in lumen of rabbit small intestine of urea

During Ischaemia of 10 Min Duration or More in vivo Uptake of cholesterol, sitosterol, monoolein, oleic acid octadecane into tissue of rat jejunum Uptake of cholesterol into tissue of rat small intestine Disappearance of jodide from rat small intestine Disappearance of fluid, sodium, chloride, glucose from dog small intestine disappearance of antipyrine, salicylic acid, L-phenylalanine, 3-O-methylglucose from rat jejunum

in vivo

in vitro

After Ischaemia of 5 Min Duration or Less

During Ischaemia of 5 Min Duration or Less in vivo Uptake of cholesterol, sitosterol, monoolein, oleic acid, octadecane into tissue of rat jejunum

130, 255-257 254 242, 254, 258 94 94 212, 312 237 173 198, 255 118 119, 198, 225 71 150 150

Reversed* Increased Increased Unchanged

Decreased Decreased Decreased Decreased Decreased Unchanged Increased Decreased Decreased Decreased Decreased

215

Decreased

248, 250 252, 253 253

291 212 119, 198

Decreased Decreased Decreased

Decreased

290

252,253 252 173

290

Decreased

Unchanged Unchanged Unchanged

Unchanged

TABLE 20. Effect of Ischaemia on Intestinal Absorption

Z m

bd

Influence of blood flow on intestinal absorption of drugs and nutrients

lntostinal ~

cw,~]~

~

/Cpw

373

v

Fro. 11. Model for the derivation of equations describing the influence of blood flow on intestinal absorption. CL, C~, Cs, C~,w, Cpwv, CpwA = concentration in intestinal lumen (bulk phase), interstitial space, serosal bath, plasma water, venous and arterial plasma water; Ael, Acw, As -- area of first barrier (mainly luminal unstirred layer and epithelium), second barrier (wall of capillaries near the epithelium), third barrier (deeper layers of intestinal wall); ksLh k8~.2 = unidirectional permeability coefficients of first barrier (lumen to interstitial space and vice versa); kcw, ks = permeability coefficients of second and third barrier; I;'8 -- total blood flow rate of intestinal loop; a = fraction flowing through capillaries near the epithelium; dotted ~ e a s : first, second, third barrier.

4.2. DERIVATION OF THE EQUATIONS DESCRIBING THE DEPENDENCE OF INTESTINAL ABSORPTION ON BLOOD FLOW

The net flux O(L/1) of a substance through the first barrier is the difference of the unidirectional fluxes. These fluxes are proportional to the area ABI of the mucosal surface, the unidirectional permeability coefficient ks~,l or kin,2, and the luminal (CL) or interstitial (Cf) concentration: d~(L/I) = knl.lAalCL -- ksmAnlCi.

(1)

This equation does not use any information about the mechanism by which the substance is transferred through the first barrier. In the case of a passive transport the unidirectional permeability coefficients are constant and equal. If an additional mechanism (e.g. active transport, solvent drag, electrical potential difference) contribute to the transfer, the ratio kal.2/kal,i is smfller or larger than unity according to the direction of this additive transport. Moreover, the unidirectional permeability coefficients can be functions of the concentration. The transfer ~ ( I / B ) from the interstitial space into the blood of the capillaries is proportional to the concentration difference between the interstitial space (CI) and the plasma water (Cpw), the surface area Acw of the draining capillaries, and the capillary permeability coefficient kcw: d $ ( I / B ) = kcw(Cl - Cpw)dAcw = d(aVaCa).

(2)

Since the concentration of the substance in the capillary increases (or decreases) from the beginning of the arterial to the end of the venous part of the capillary, the differential form is used. The change of the transfer rate riO(liB) is equal to the change of the amount of substance in the blood d(c~VBCB), where Ca represents the blood concentration, I?~ the total blood flow rate of the intestinal loop, and a the fraction of blood flowing through the draining capillaries. Introducing al = CBICpw,

(3)

374

D. WINNE

the concentration ratio blood to plasma water (covers the intravasal distribution: protein binding and storage in red cells), we obtain the following differential equation: dCl, w =

kcw a a i(/'8 ( C P w - C1)dAcw.

(4)

Assuming that C~ is constant the following solution is obtained: Ct,w v - C v w A = (el - CI,wA)E!

(5)

with

El

= 1 - e l(-kcwAcw)l('~a''i's)l = r Cl"wv" -

L

CpwA ] J"

(6)

Cpwv and CPWA are the concentrations in the venous and arterial plasma water, respectively. Since ~(IIB) is the difference between the amount of substance in the venous and arterial blood: qb(I/B) = ct (:B(Cnv - CSA) = otal fzn(Cpwv - CPWA),

(7)

we obtain by inserting equation (5) into equation (7): 6 ( I / B ) = aa~El V'B(G - CpWA).

(8)

According to equation (6) (right hand side) the quantity E~ is the ratio of two differences: venous minus arterial plasma water concentration and interstitial minus arterial plasma water concentration. E~ characterizes the deviation from the concentration equilibrium at the venous ending of the capillary. If the equilibrium is reached at this point (Ce~, = CD, El becomes unity. The transfer ¢P(I/S) through the third barrier is assumed to be proportional to the concentration difference between the interstitial space (CD and the serosal bath (Cs), the serosal area As, and the permeability coefficient ks of the third barrier:

(9)

dp(l[ S) = ksAs( Ct - Cs).

In the steady state and in the absence of metabolism the transfer rate through the first barrier is equal to the sum of the transfer rates through the other barriers:

4~(LII) = 4~(I/B) + 4~(I/S).

(IO)

After introducing equations (1), (8) and (9) into equation (10) we can solve the equation for the unknown interstitial concentration: Cl = k m . i A m C L

+ txaiEl ~'sCewA + k s A s C s

kal,2Am + aa,Ej ¢8 + ksAs

Of)

Inserting equation (11) into equations (1), (8), or (9) we obtain after rearranging the following equations for the dependence of the absorption rates on blood flow rate: disappearance

rate .from intestinal

lumen

[ ctalEl "~'aCPwA+ ksAsCs 1 dp(L/l) =

1

kal.lAm

p_kin,2

I

k~l,~cratE1 ("B + ksAs

.2)

Influence of blood flow on intestinal absorption of drugs and nutrients

375

appearance rate in intestinal venous blood

Ct_r~.l 6(I[B) =

Lkm,, 1

k,,,,A._____~l+

1c..,.,+

ksAs ksAs Cs kBl~lAmJ ka,,,Aa-------~l {kal.2 + ksAs .'~ /Iota,E, fZ~) \kan.I k ~ . l A a l / /

(13)

appearance rate in serosal bath dp(I/S) =

cL+

C.wA [k.,.2 -alE,' s]p kBl,lAsl

- LkBl,14 ~kBl,,Am J ~S ksb2 + aa,E, VB 1 + km,, ksl.jAsl kBLIABI ksAs

(14)

More general equations have been derived by Winne (197 l a), see also the theoretical treatments of Winne and Ochsenfahrt (1967) and Winne (1970b). For special cases (km.~ = kma = ks,; CpwA = Cs; CpwA = Cs = 0; ks = 0) simpler equations can easily be derived. Since the apparent first-order absorption rate constant is a function of the gastrointestinal absorption, analogous equations can be derived for the blood flow dependence of this rate constant (Ochsenfahrt and Winne, 1967; Winne, 1978). 4.3. PREDICTIONS BASED ON THE MODEL Equations (12) through (14) are too complex to deduce easily the influence of blood flow on intestinal absorption. Therefore, a simple case is discussed: serosal appearance neglected (ksAs = 0), passively transported substance (ksm.,= kB~a= ka0. From equation (12) or (13) we obtain for the absorption rate O(L/B):

4~(L/I) = ck(I[B ) = ,k ( L / B ) =

C L -- C p w A

1 kmAm

1 aa,E! V8

(15)

The intestinal absorption is proportional to the concentration difference between the intestinal lumen (bulk phase) and arterial plasma water. The denominator of equation (15) can be interpreted as transport resistance. According to the two terms in the denominator the total resistance can be divided into two partial resistances. The first term, the reciprocal of the permeability of the first barrier, represents the resistance from the bulk phase of the intestinal lumen to the interstitial space. The second term represents the resistance of the draining system and comprises the resistance of the capillary wall (in the quantity E0 and the blood flow rate which determines the effectiveness of the drainage. In the case of a highly permeable substance (large permeability coefficient ks0 the first term in the denominator is small and can be neglected (1/ka,AB~-~ 0). The second term determines the absorption rate:

ck(L/ B) = otalEi ~/B(CL -- CpwA).

(16)

The absorption is proportional to the blood flow rate al?8 in the draining capillaries: blood flow limited absorption. In the case of a substance with a low permeability (small permeability coefficient kBi) the first term in the denominator of equation (15) becomes large, so that the second term with the blood flow plays no or only a small role. The absorption is independent or nearly independent of blood flow: blood flow independent absorption: 4,(L/B) = kB,ABI(CL- Cpw,O.

(17)

In the case of a substance with an intermediate permeability coefficient the second

376

D. WINNE

term in the denominator of equation (15) is small at high blood flow rates and large at low rates. That means, the absorption rate increases with increasing blood flow rate especially at low flow rates, but the influence of blood flow is less at higher rates. Figure 12a demonstrates clearly the dependence of the appearance rate in the intestinal venous blood on blood flow and the transition from blood flow independent to blood flow limited absorption, if the absorbability of the substances increases. The curves have been calculated by the following equation where the permeation to the serosal surface has not been neglected (from equation (13) with CpwA= Cs = O, km.I = kin.2 = k~l):

CL ~(I/B) =

1.___L__+ 1 + (ksAs)/(kmAm)" kBiAm aazEl Vb

(18)

The corresponding equation for the disappearance rate is the following one:

4~(L/I) =

CL

1

1

(19)

kBjABm aalEi (/'a + ksAs The d e p e n d e n c e of the disappearance rate on blood flow is diagrammed in Fig. 12b. The permeability coefficient ka~ is varied. In contrast to the appearance rate, the disappearance rate does not approach zero as the blood flow rate decreases. While the second term in the denominator of equation (18) increases infinitely resulting in a zero appearance rate at zero blood flow rate, the corresponding term in equation (19) approaches l/ksAs and a finite disappearance rate is obtained at zero blood flow rate. The quantity 1/ksAs represents the resistance of the deeper layers in the intestinal wall (third barrier). At zero blood flow rate the disappearance rate from the intestinal lumen is equal to the appearance rate in the serosal bath, provided metabolism and accumulation are absent. With increasing blood flow rate the serosal appearance decreases (Fig. 13a), since the drainage becomes more effective. The curves of Fig. 13a have been calculated by the following equation:

4,(IIS) =

cL 1 1 + (aa IE, ("a/kmABi)" ks lAB i ksAs

a

(20)

b

.2: mllmin.g

/1 /

,5

"21rnl/rn~'g/1/5

In .g ®

"

I

I

/ /

I/

.2 X <

"~

~o

.1

~o 1

mllmin.g 2

Venous Outflow Rate

0

1

mlln'm.g 2

Venous Outflow Rate

FIG. 12. The dependence of the appearance rate in intestinal venous blood and of the disappearance rate from intestinal lumen on blood flow rate and permeability of first barrier according to the model. Curves calculated by equations (18) (panel a) and (19) (panel b) with ddCL as ordinate, I?a as abscissa, aalEa = 0.2, ksAs = 0.07 ml/min g; kslAsl varied.

Influence of blood flow on intestinal absorption of drugs and nutrients

377

o

•

a

~ O.

.

2

0

¢'.20 ' roll min.g

mllmin, g

-

P

m

~ .lS

.15 "

-~ kst Ai 0 .lO- ml I m i n g

0

.05

-; /

o ;.~/~,.g2 V e n o u s O u t f l o w Rate

c

.10.

0

5

.

.

g/ 2

,

V e n o u s O u t f l o w Rate

®

.

0

._~ .10

e . 2 0 " mllmin.g

~

km.2/kmj

~

u~. 05' " , , - 0 ~~

®

b

0¢

d

®.'10 ~ ml/min'g

.4

~

.

.2

0-.05'

i~ .o5.

1 •

g~

o5

0

0 1 2 V e n o u s O u t f l o w Rate

0 .1 .2 .3 V e n o u s O u t f l o w Rate

F~G. 13. The dependence of the intestinal absorption rate on blood flow rate, permeability of

first barrier, ratio of unidirectional permeability coefficients, fraction of 'effectve' blood flow, and intravasal distribution according to the model. Curves calculated with 0/C, as ordinate, I?a as abscissa, cta~Ei = 0.2, ksAs = 0.07 ml/min g; panel a: equation (20), kB,Asi varied; panel b: equation (21), kBM.iAsl=0.1 ml/ming, kBI,2/kBIj varied; panel c: equation (19), ksl.jAs~ = 0.1 ml/min g, El = 1, aal varied; panel d: equation (16), CewA= 0, El = 1, aal varied. The influence of the quantities ka,~/kalj, a, a, shall be investigated by the following equation (from equation (12) with k, = O, CPwA = Cs = 0):

c~ 4,(L/I) =

1 ks=jAB1

+ kBi.2

]

(21)

kB,.l a a l E i "V'B+ ksAs

In the presence of an additive transport mechanism (e.g. active transport) working in the direction lumen to blood the ratio kBi.2/ks,., of the unidirectional permeability coefficients falls below unity. If the lumen-to-blood flux increases relatively to the blood-to-lumen flux (decreasing ratio ks,.21kB~.l), the disappearance rate increases, especially at low flow rates (Fig. 13b). The shape of the curves becomes linear and parallel to the abscissa. Therefore, the influence of blood flow on the absorption of an actively transported substance is very low provided the oxygen supply is not impaired. This can be derived directly from equation (21). With decreasing ratio kB,~/k81j the second term in the denominator becomes smaller, so that the influence of blood flow decreases. In the case of kB~.z/kB~., = 0 this term vanishes: blood flow independent absorption (horizontal line in Fig. 13b). A condition for an influence of blood flow on the disappearance rate is that the unidirectional flux from blood to lumen does not vanish (kBi.2 # 0). More exactly: the blood-to-lumen flux must inc r e a s e - - n o t necessarily linearly--with increasing interstitial concentration. If kB,.2/kB=., increases above unity (active transport directed towards the lumen), the disappearance rate decreases as shown by the shift of the curves in Fig. 13b to the abscissa. The curve for a substance with an intermediate permeability coefficient is shifted to the left and to higher values (Fig. 13c), if a, the fraction of blood flowing through capillaries near the epithelium = 'effective' mucosal blood flow, is increased. The horizontal part of the curve, where the influence of blood flow on absorption is zero, is reached at lower flow rates. The same effect is observed, if the protein binding or (and) the distribution into the red cells increases (increasing a0. The corresponding

378

D. WINNE

curves for th e appearance rate in the intestinal venous blood are similar but they cross the origin. In the case of a highly permeable substance (1/kin-,0), the absorption increases linearly with the blood flow (see equation (16) and Fig. 13d; in this example the transfer to the serosal surface is neglected: ks = 0). The steepness of the curves increases as t~ increases. Therefore, the mucosal blood flow can be determined by measuring the absorption rate of a highly permeable substance. The corresponding curves for the disappearance rate are similar with the exception that they do not intersect the ordinate in the origin but in a point above it. For the influence of blood flow on the 'secretion' of a substance, more strictly on the appearance rate in the intestinal lumen, generally similar curves are obtained as for the disappearance rate. Therefore, the curves in Fig. 12b also represent the dependence of the luminal appearance on blood flow varying the permeability of the first barrier (CpwA = Cs). Analogously Fig. 13c and d demonstrate the influence of a a~. If the ratio km~Jkm,i is varied, we obtain curves for the luminal appearance rate as shown in Fig. 12b and not as in Fig. 13b. 4.4. PREDICTIONS BASED ON MODIFICATIONSOF THE MODEL

4.4.1. N o n - C o n s t a n t Fraction o f M u c o s a l B l o o d F l o w The curves in Figs. 12 and 13 have been calculated under the assumption that a, the fraction of blood flowing through capillaries near the eipthelium = ratio of 'effective' mucosal blood flow rate to total flow rate, does not change with increasing or decreasing total blood flow rate. Extensive investigations in cats and dogs, however, showed that this fraction is not constant (Folkow et al., 1964; Rutherford et al., 1970; Biber et al., 1973b, c; Lundgren and Svanvik, 1973; Svanik, 1973a, b; Fara and Madden, 1974, 1975; Norris and Sumner, 1974; Fara et al., 1975; Yu et al., 1975; Hult6n et al., 1977). According to the method used to vary the blood flow the fraction is different and/or changes with the total flow rate (see also Fig. 5b): the distribution pattern of blood in the intestinal wall is variable. Figure 14a shows the absorption curves for a substance with intermediate permeability in the case of a non-constant a calculated by the following equation (compare with equation (15): 4~(L/B) =

1 kalAal

CL

l

(22)

(ao + A a l / B ) a , E l ( l ~

If the fraction a increases with increasing total blood flow rate (Aa >0), the appearance rate in the intestinal venous blood increases more rapidly: the curves are shifted to the left and to higher values. If the fraction a decreases with increasing total flow rate (Aa < 0), the curves become flatter and can decrease at high flow rates. In the case of a highly permeable substance we obtain a deviation from linearity (Fig. 14b, compare with Fig. 13d), if the fraction t~ varies with the total blood flow rate. If a increases, curves with convex shape, and if a decreases, curves with concave shape are obtained. 4.4.2. Villous Countercurrent E x c h a n g e In a series of investigations, Lundgren and co-workers have shown that in the intestinal villi of the cat highly permeable substances are shunted extravascularly between the venous and arterial limbs, so that a countercurrent exchange is built up (Kampp and Lundgren, 1966a, b, 1968; Lundgren and Kampp, 1966; Lundgren, 1967, 1970, 1974; Kampp et al., 1968b, c; Haglund et al., 1972, 1973b; Jodal, 1973, 1974; Jodal and Lundgren, 1973b; Svanvik, 1973a; Haglund and Lundgren, 1974) Similar results have been obtained in the dog (Bond et al., 1977). An effective countercurrent exchange can apparently be found only in fingerlike villi. In the rabbit and in the rat, however, no signs of a countercurrent exchange have been observed (Levitt and Levitt, 1973; Bond et al., 1974; Levitt et al., 1974). In the rodents the villi have a leaf-

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FIG. 14. Panel a--c: The dependence of the appearance rate in intestinal venous blood on blood flow rate with variable fraction of 'effective' blood flow or in the presence of a counter current exchange according to modifications of the model. Curves calculated with ~/CL as ordinate, I?B as abscissa, a=0.2, a~= 1, E~ = 1; panel a: equation (22), kstAsl=O.lml/ming, Aa varied; panel b: equation (22), kB~ABI= 10m//ming, Aa varied; panel c: equation (23), kB~ABt = 10mi/ming, P~FE varied. Panel d: Dependence of the disappearance rate from intestinal lumen on blood flow rate at different luminal and plasma water concentration. Curves calculated by equation (12) with 6 as ordinate and relative mesenteric blood flow rate as abscissa (100 per cent = 73.8 ml/min), with kB~Aa, = 103.5 ml/min, aa,E, = 0.3, ksJka,., = 0.86, ks,As = 8.036ml/min; curve A: CL = 140m equiv/litre, Cs = CpwA = 0, corresponds to lumen-to-blood flux; curve B: CL = C~,wA= Cs = 140 m equiv/litre, corresponds to net flux; curve C: CL = 0, CPwA= Cs = 140 m equiv/iitre, corresponds to blood-to-lumen flux.

or tongue-like shape, they are also trapezoidal or triangular (Kulenkampff, 1975; Winne, 1977a). In the n o n - s t e a d y state (single administration) the c o u n t e r c u r r e n t exchange retards the absorption or secretion of substances, in the steady state the absorption or secretion rate is reduced (Lundgren and Svanvik, 1968; Biber et al., 1973c; Svanvik, 1973a, c). The oxygen supply of the tips of the villi is diminished and this m a y be the cause for the lesions first o b s e r v e d in the tips of the villi in h y p o t e n s i o n (Lundgren, 1967; K a m p p et al., 1967, 1968a; Haglund, 1973; Haglund et al., 1973a, 1975). The countercurrent exchange builds up a steeper apical-basal concentration gradient in the villi (Lundgren and K a m p p , 1966; K a m p p et al., 1968c; Haijam/ie et al., 1971, 1973; Jodal, 1973; Jodal and Lundgren, 1973a). The a b s o r b e d sodium is a c c u m u l a t e d in the apical part of the villi and thereby increases the osmotic pressure. T h e r e f o r e , it m a y play a relevant role in the absorption of w a t e r (Haljam/ie et al., 1971, 1973; Jodal, 1974; Jodal and Lundgren, 1975). Figure 14c shows the influence of the countercurrent exchange on the absorption of a highly p e r m e a b l e substance. The curves have been calculated by the following equation: ~b(L/B) =

CL 1 ks,ABI

(23)

1 + ( P E F ~ E i / a a l I;'B) ' a a l E i fib

where PEFB characterizes the permeability of the exchange region (PE = permeability coefficient, FB area of the e x c h a n g e region). F o r a detailed derivation of the equation see Winne (1975). With increasing permeability of the exchange region, increasing PEFE, the absorption rate decreases. The curves m o v e to the abscissa and b e c o m e convex. T h a t means, at low flow rates the countercurrent exchange has its highest

380

D. WINNE

efficiency. T h e curves have been calculated under the assumptions that a is constant and that the blood flow rate in the villi is increased only by increasing the linear flow rate in the capillaries and not by increasing the number of open capillaries, If the blood flow rate is increased only by increasing the number of open capillaries, the absorption rate increases linearly for a highly permeable substance like the curves in Fig. 13d, since the efficiency of the counter current exchange is not changed. In reality the two factors, linear flow rate and number of open capillaries, contribute simultaneously to the change of villous blood flow rate. Moreover, the villous and total flow rate do not change in paralled (non-constant a), so that the relationship between absorption and blood flow is very complicated. 4.4.3. Time Dependent Absorption In the experiments illustrated in Figs. 6 and 8 the relationship between blood flow and absorption depends apparently on the sequence of the blood flow change. In these investigations it has been observed that in spite of a constant--intermediate--blood flow rate the absorption rate decreases more or less with time. Substances with a pronounced temporal decrease of absorption show also a considerable divergence of the blood flow-absorption relationship. Therefore, the consequences of a temporal decrease of the epithelial permeability kBt,lAal or of the fraction ot of blood flow on intestinal absorption shall be investigated theoretically:

kBt.lAsi = (kBt.tAst)o e -~t,

(24)

ot = t~o e -~t.

(25)

Arbitrarily, an exponential function has been chosen, since the quantities tz and ksl.tAB, can be only positive. The quantity 3, characterizes the temporal change and t is the time. Crossing curves are obtained, if kBt,tAa~ or ot decreases with time and 3, is about equal in the experiments with decreasing and increasing blood flow rate (Fig. 15). If 3, is kept constant for the experiments with decreasing blood flow and is increased in the experiments with increasing blood flow, the two curves diverge (Figs. 15a and b). The divergence becomes more pronounced as the difference between the temporal decrease increases. Similar curves are obtained whether a temporal decrease of the epithelial permeability or of the fraction a is assumed. Figures 15c and d show the effect of reducing the quantity 3, only in the experiments with decreasing blood flow. If 3, is equal, the curves are crossing in their centre. If 3, is smaller in the exiaeriments with decreasing blood flow, the crossing point shifts to the left. 4.5. COMPARISONOF THEORETICALPREDICTIONS WITH EXPERIMENTALDATA

It can be recognized that the experimental data obtained in the rat jejunum can be well described by the model derived in Section 4.2 when comparing Fig. 12 with Figs. 3b-d, 4, 7c, 9a-b and Fig. 13a with the curves for the serosal appearance in Fig. 9. Also the curves in Figs. 2a, 7a, and 7b coincide with the predictions of the nonmodified model. It should be noticed that curves with a concave shape can be obtained in the case of a constant fraction a and an intermediate epithelial permeability (Fig. 12) as well as in the case of a decreasing fraction a with increasing blood flow rate (Fig. 14a, b), the epithelial permeability can be high or intermediate. Since krypton is a highly permeable substance, the resistance of the first barrier to it should be low. A linear relationship between the vascular appearance rate and the blood flow rate is, therefore, expected and the curve should pass through the origin (Figs. 12a, 13d). Deviations from linearity are interpreted by a variatiofi of the fraction a (Figs. 5b, 14a, b) for example the convex shape of the curve in Fig. 2c can be explained by an increase of the fraction a with increasing total blood flow rate (compare with Fig. 14b). The curve of Fig. 2b can be interpreted in the same sense. For highly permeable substances we have to consider also the counter current

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FtG. 15. The dependence of the appearance rate in intestinal venous blood on blood flow rate and temporal decrease of epithelial permeability (left panels) or of fraction of 'effective' blood flow (right panels) according to a modification of the model. Curves calculated with ~/CL as ordinate, ~'a as abscissa, a,E~ = l, ksAs = O, and (kat.tAa,)o = kaLiA81 = 0.1 ml/min g changing ~'8 from 0.2 to 1.0 to 1.8 ml/min g and vice versa (see arrows); panel a: equations (21) and (24), a = 0.2, kal.2/kaLm = l, y for increasing blood flow varied; panel b: equations (21) and (25), a0 = 0.2, kBm.2/k~l.l = 1, y for increasing blood flow varied; panel c: equations (21) and (24), a = 0.2, kaj.2/ka~.~ = 2/7, y for decreasing blood flow varied; panel d: equations (21) and (25), s 0 = 0.2, kal~/kat.i = 0.1, y for decreasing blood flow varied.

exchange, if the experiments are carried out using species with fingerlike villi. Curves with c o n v e x shape are predicted, if the increase of the villous blood flow rate is based mainly on an increase of the linear velocity in the villous vessels (Fig. 14c). Therefore, the course of the curve in Fig. 2d has been interpreted as effect of a counter current exchange. It should be noted that the abscissa of this diagram represents the villous blood flow rate; the influence of the fraction a is already eliminated. The curve in Fig. 2d deviates from the curves in Fig. 14c--the same curves are obtained, if the absorption rate is plotted vs the villous flow rate, since a constant a has been assumed in the calculation of the curves of Fig. 14c. The curves in Fig. 14c start at the origin with a c o n v e x shape, while the extrapolation of the curve in Fig. 2d to the origin results in a concave shape for the section near the origin. T h e r e f o r e , the curve in Fig. 2d can be interpreted by equation (23) only if the exchange permeability P~FE increases non-linearly with increasing villous flow rate. The situation seems to be more complicated than assumed in the model on which equation (23) is based. A correspondence between the predicted and the experimental curves do not prove the conclusiveness of the theoretical model. For example, the curve in Fig. 3a does not deviate appreciably from the steep curves in Fig. 12, especially if the variability of the experimental data is taken into account. Therefore, the curve can be explained by the non-modified model. Using additional information, the same absorption data can be plotted vs the villous blood flow rate (Fig. 2d). The interpretation of the resulting curve by the model even after considering a counter current exchange is not satisfactory as described above. The d e p e n d e n c e of the net flux and the unidirectional fluxes of sodium on blood flow (Fig. 7d) cannot be interpreted in a simple way. The greater influence of the blood flow rate on the unidirectional fluxes than on the net flux agrees with the predictions of the model (Fig. 14<1). The change of the net flux from positive to negative values at low flow rates means that the ratio of the unidirectional fluxes increases from values below, to values above unity. Simultaneously a variation of the ]PT Vol. 6, No. 2--K

382

D. WINNE

fraction a and presumably of other factors not included in the model have to be taken into account. The curves in Figs. 6, 8, 9c-d demonstrating the different relationship between blood flow rate and absorption in experiments with decreasing and increasing blood flow can be explained by a different temporal decrease of the permeability of the first barrier kin.lAin or of the fraction a under the two experimental conditions. The different types of the experimental curves can be found in Fig. 15 where the theoretical curves are diagrammed. The temporal decrease of kal.lAm or a causes the same type of curves. Therefore, from the shape of the curves alone it cannot be decided which quantity changes. The real cause of the temporal decrease of the absorption in the experiments with rat jejunum is not yet clarified. The following factors may contribute more or less to the phenomenon: firstly, increasing thickness of the unstirred layer by mucus secretion, secondly, increasing water content of the interstitial space (increasing diffusion distance), thirdly, lowering of the blood flow rate through the draining capillaries=change in distribution pattern of blood (decreasing factor a). The greater temporal decrease of the absorption in the experiments with increasing blood flow rate may be due to the first period with low flow rate. After this period the initial blood flow pattern is probably not restored, though the total blood flow rate has been raised to the initial value. Moreover, the low blood flow rate in the first period may impair active transport mechanisms by insufficient oxygen supply. From experiments with ischaemia (Section 3.9) it is known that the impairment of the absorption is not restored immediately after termination of the ischaemia, even more the alterations may be intensified temporarily. An attempt has been made to interpret the experimental findings by one theoretical model using some modifications where necessary. There are other, more or less similar, models which have been applied successfully to experimental data concerning the relationship between blood flow and intestinal absorption (see review of Winne, 1978). The models simplify the real situation accentuating different aspects, so that several models fit the experimental data equally well and it is difficult to decide between them (Winne, 1978). In the following the main factors and quantities are listed which have to be considered in the interpretation of experimental data describing the relationship between intestinal absorption and blood flow: 1. total blood flow rate (I~'B), 2. fraction of flow rate through the draining capillaries (a), 3. protein binding and distribution into red cells (aj), •4. permeability of the first barrier = unstirred layer and epitnelium (kalAm), 5. concentration gradient in capillaries (E~), 6. asymmetry of the permeation through the first barrier = ratio of the unidirectional permeability coefficients (kal~/km.m 7. dependence of intramural blood flow pattern on total flow rate, time, method of changing blood flow, preceding events (non-constant or), 8. change of epithelial permeability with time or secondarily to blood flow changes, e.g. temporary insufficient oxygen supply (non-constant ks1).

5. CONCLUDING REMARKS The equations derived in Section 4.2 describe the dependence of intestinal absorption on blood flow rate, but only the drainage effect of the blood flow is covered by these equations. Comparison of in vivo results with in vitro data demonstrate the different effects and the importance of the blood flow. The drainage effect prevents the accumulation of the absorbed substance' (Davidson and Leese, 1977) and fluid in the intestinal wall, so that the concentration at the basal side of the epithelial cells do not rise considerably above the arterial concentration (Parsons, 1975a). Under in vitro conditions the subepithelial tissue functions as a thick unstirred layer: generally, the concentration at the basal side of the epithelial cells does not coincide with the serosal

Influence of blood flow on intestinal absorption of drugs and nutrients

383

concentration. The higher intramural concentration in vitro m a y influence the m e t a b o l i s m of the cells, e.g. the metabolic rate of glucose and lactate production is higher in vitro than in vivo (Parsons, 1975a; H a n s o n and Parsons, 1976). In vitro the transfer of highly lipid-soluble c o m p o u n d s through the subepithelial tissue represents the rate-limiting step (Gibaldi and G r u n d h o f e r , 1972). A positive and negative water net flux increases or d e c r e a s e s the volume flow through the capillaries near the epithelium and increases or d e c r e a s e s in this w a y the absorption rate of highly p e r m e a b l e substances. Thus, the blood flow can contribute to solvent drag p h e n o m e n a ( O c h s e n f a h r t and Winne, 1972, 1973; K o j i m a and Miyake, 1975). Another main function of the blood circulation is the supply of oxygen and nutrients. In vitro the oxygen and the nutrients h a v e to diffuse f r o m the mucosal bulk phase or the serosal bath through the mucosal unstirred layer or through the subepithelial tissue to the epithelial cells. Because of the villous structure of the intestinal m u c o s a the diffusion distances are different and it seems that in vitro the oxygen supply is often not optimal (Ochsenfahrt, 1973; Fisher and Gardner, 1974a; Dugas and Crane, 1975; H a n s o n and Parsons, 1976). In vivo the oxygen is supplied directly to the basal side of the epithelial cells. The hydrostatic pressure in tissue p r o d u c e d by the capillary pressure can be of i m p o r t a n c e for the net transfer of fluid across the intestinal epithelium. This is indicated by the different effect of laxatives in vivo and in vitro. The administration of oxyphenisatin and other substances abolishes the sodium and fluid absorption in the colon in vitro and in vivo. H o w e v e r , only in vivo a net flux into the lumen can be induced by higher concentrations (Forth et al., 1966; Nell et al., 1973; E w e and H61ker, 1974; R u m m e l et al., 1975; Wanitschke et al., 1977b). If in vitro the physiological hydrostatic pressure on the contraluminal side of an isolated rat colonic m u c o s a is simulated b y administering a pressure of 5 cm water, a 'secretion', i.e. a net transfer of fluid and sodium chloride into the mucosal bath, is also o b s e r v e d in vitro (Wanitschke et al., 1977a). F o r details see R u m m e l et al. (1975). REFERENCES Numbers after each reference refer to numbers given in Tables. AMBROMOVAOE,A. M., SHAH,U. and HOWARD,J. M. (1971) Xylose and inulin absorption. Archs. Surg. 102: 496-500. (1) ATKn~SON,R. M., PARSONS,B. J. and S~rrrH, D. H. (1957) The intestinal absorption of glucose. J. Physiol., Lond. 135: 581-589. (2) AUSTEN, W. G. and MCLAUGHLIN, E. D. (1965) In vitro small bowel perfusion. Surg. Forum. 16: 359-361.

(3)BACAN~, M. B. and BECK,J. S. (1964) Regional blood flow measurement in vivo for a definable geometry. Am. J. Physiol. 206: 962-966. (4) B ~ t , W. H. and I~EGELMAN,S. (1970) Intestinal drug absorption and metabolism I: comparison of methods and models to study physiological factors of in vitro and in vivo intestinal absorption. J. pharra. Sci. $9: 154-163. (5) I~ARROWMAN,J. and ROBERTS,K. B. (1967) The role of the lymphatic system in the absorption of water from the intestine of the rat. Q. Jl. exp. Physiol, 52: 19-30. (6) B ~ U M , JR., R. J., BElUcowrrz, D. M. and HOLLENnERG,N. K. (1974) A simple radioactive microsphere method for measuring regional flow and cardiac output. Invest. Radiology. 9: 126-132. (7) BENSONJR., J. A., LEE, P. R., SCXOL~, J. F., ICa~,K. S. and BOLL~AN,J. L. (1956) Water absorption from the intestinevia portal and lymphatic pathways. Am. I. Physiol. 184:441 A.aA..(8) BENY0, I., JAKAB, F., SUGA~R, I. and SzAn0, G. (1977) The effect of acidifying the duodenal contents on splanchnic blood flow. Acta Hepato-Gastroenterol. 24: 201-204. (9) BEUBLER, E. and JUAN, H. (1977) The function of prostaglandins in transmucosal water movement and blood flow in the rat jejunum. Naunyn-Schmiedebergs Arch. Pharmak. 299: 89--94.(I0) BEUBLER, E. and LEMBECK, F. (1976) Methylxanthines and intestinaldrug absorption. Naunyn-Schmiedebergs Arch. Pharmak. 292: 73-77. (I I) BmER, B. (1974) The effects of intestinalvasodilator mechanisms on the rate of SSKr absorption in the cat. Acta physiol, scand. 90: 578--582.(12) BIBER, B., L ~ R E N , O., STAGE, L. and SVANVlK, J. (1973a) A n indicator-dilutionmethod for studying intestinalhemodynmnics in the cat. Acta physiol, scand. 87: 433--447.(13) BmER, B., LUNIX~REN, O. and SVANVIK, J. (1969) A n indicator-dilutiontechnique for studying mean transit time and blood flow in the mucosa-submucosa of the small intestine.Acta physiol, scand. Suppl. 330: 99. (14) BmER, B., LUNDOREN, O. and SVha,PCIK, J. (1973b) Intramural blood flow and blood volume in the small intestine of the cat as analyzed by an indicator---dilutiontechnique. Acta physiol, scand, g7: 391---404. (15)

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BmER, B., LUNDGREN,O. and SVANVIK,J. (1973c) The influence of blood flow on the rate of absorption of SSKr from the small intestine of the cat. Acta physiol, scand, gg: 227-238. (16) BOCK, K. W. and WINNE, D. (1975) Glucuronidation of l-naphthol in the rat intestinal loop. Biochem. Pharmac. 24: 859-862. (17) BOLLMAN, J. L., CAIN, J. C. and GRINDLAY,J. H. (1948) Techniques for the collection of lymph from the liver, small intestine, or thoracic duct of the rat. 2. Lab. clin. Med. 33: 1349-1352. (18) BOLTON, J. E., MUNDAY,K. A. and PARSONS,B. J. (1975a) The effects of anglotensin on fluid transport and blood flow in rat jejunum. J. Physiol., Lond. 244:27 P-28 P. (19) BOLTON, J. E., MUNDAY, K. A., PARSONS, B. J. and YORK, B. G. (1975b) Effects of angiotensin II on flu/d transport, transmural potential difference and blood flow by rat jejunum in vivo. ]. Physiol., Lond. 253: 411-428. (20) BOND, J. H., LEVITT, D. G. and LEVITT, M. D. (1974) Use of inert gases and carbon monoxide to study the possible influence of counter current exchange on passive absorption from the small bowel. J. clin. Invest. 54: 1259-1265. (21) BOND, J. H., LEVITT, D. G. and LEVITT, M. D. (1977) Quantitation of countercurrent exchange during passive absorption from dog small intestine--evidence for marked species differences in efficiency of exchange. ]. clin. Invest. 59: 308-318. (22) BOYD, C. A. R. (1977a) Amino acid inhibition of the exit of monosaccharide from the intestinal epithelium. J. Physiol., Lond. 271:48 P-49 P. (23) BOYD, C. A. R. (1977b) Vascular flow and the compartmental distribution of transported solutes within the small intestinal wall. In: Intestinal Permeation, pp. 41-47, KRAMER, M. and LAUTERBACH,F. (eds.)., Proceedings of the Fourth Workshop Conference Hoechst, Schioss Reisensburg, 19-22 October, 1975 (Workshop Conferences Hoechst Volume 4), Excerpts Medics, Amsterdam-Oxford. (24) BOYD, C. A. R., CHEESEMAN,C. I. and PARSONS D. S. (1975) Amino acid movements across the wall of anuran small intestine perfused through the vascular bed. J. Physiol., Lond. 250: 409-429. (25) BOYD, C. A. R. and PARSONS, D. S. (1976) Movement of sugars between compartments of vascularly perfused intestine. J. Physiol., Lond. 258:12 P-13 P. (26) BOYD, C. A. R. and PARSONS, D. S. (1978) Effects of vascular perfusion on the accumulation, distribution and transfer of 3-O-methyl-D-glucose within and across the small intestine. J. Physiol., Lond. 274: 17-36. (27) BROBMANN,G. F., JACOBSON,E. D. and BRECHER,G. A. (1970) Intestinal vascular responses to gut pressure and acetylcholine in vitro. Angiologica 7: 129-139. (28) BUCKBERG, G. D., LUCK, J. C., PAYNE, D. B., HOFFMAN, J. I. E., ARCHIE, J. P. and FIXLER, D. E. (1971) Some sources of error in measuring regional blood flow with radioactive microspheres. J. appl. Physiol. 31: 598-604. (29) COBURN, R. F. (1968) Carbon monoxide uptake in the gut. Ann. N.Y. Acad. 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