(D) Routes of delivery: Case studies

Advanced Drug Delivery Reviews, 8 (1992) 237 251

237

Elsevier Science Publishers B.V. ADR 00109

(D) Routes of Delivery: Case Studies (4) Rate-controlled rectal peptide drug absorption enhancement A . G . de Boer, E.J. van Hoogdalem* and D.D. Breimer Division of Pharmacology, Centre for Bio-Pharmaceutical Sciences, Sylvius Laboratory, State University of Leiden, Leiden, The Netherlands (Received March 11, 1991) (Accepted May 6, 1991)

Key words: Peptide; Absorption; Rectum; Enhancement; Rate-controlled; Concentration-effect relationship; Mucosal damage

Contents Summary .........................................................................................................

238

I. Introduction ............................................................................................

238

II. Potentials and limitations of rectal peptide drug delivery ................................... 1. Physiology and histology of the rectal cavity ............................................. 2. Venous drainage of the rectum ............................................................... 3. Lymphatic drainage of the rectum .......................................................... 4. Bioavailability and transport routes of peptide drugs .................................. 5. Metabolic degradation of peptides .......................................................... 6. Other factors influencing rectal peptide drug absorption ..............................

238 238 239 239 239 241 242

III. Rate-controlled rectal peptide delivery and absorption enhancement .................... 1. Rate-controlled rectal drug delivery ......................................................... 2. Rate-controlled rectal peptide drug delivery and absorption enhancement ........ 3. The influence of the concentration-effect relationship of an enhancer on the plasma concentration-time profile of a peptide drug ...................................

242 242 242 244

Abbreviations: AUC, area under the curve; DGAVP, desglycinamide arginine vasopressin; HulFNI3, human fibroblast interferon-13; i.v., intravenous; STDHF, sodium tauro-24,25-dihydrofusidate. *Present address: Royal Gist-Brocades NV, Delft, The Netherlands. Correspondence: A.G. de Boer, Division of Pharmacology, Centre for Bio-Pharmaceutical Sciences, Sylvius Laboratory, State University of Leiden, Leiden, The Netherlands. Fax: (31) (71) 276292.

238

A.G. D E B O E R ET AL. IV. Limitations o f rectal absorption enhancement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

247

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

249

Summary The potentials and limitations of rectal peptide drug delivery as an alternative to parenteral administration are discussed. Several absorption enhancers have been shown to increase considerably the systemic availability of peptide drugs on rectal administration, which may vary with the rate of delivery of enhancer and peptide. It is emphasized that the concentration-effect relationship of enhancers should be investigated in terms of their influence on area under the plasma concentration-time curve of the peptide drug. Theoretical simulation experiments were performed to illustrate this. Furthermore, it is stressed that safety evaluation of enhancers in terms of causing potential mucosal damage should be given more attention.

I. Introduction Many (endogenous biologically) active peptides have been discovered and identified and are presently produced by chemical synthesis or biotechnology [1]. However, their clinical application is still limited because their absorption, following non-parenteral administration is poor due to the presence of major physical and metabolic barriers. These barriers are of major importance, since peptides do hardly pass biological membranes and are in general very susceptible to metabolic breakdown. Small changes in their structure may lead to less pharmacologically active compounds or compounds which are devoid of activity. Invasive routes of administration may be acceptable when peptides have to be given for short periods of time; however, for chronic administration noninvasive alternatives are to be found. In this review the potentials and limitations of the rectal route, as an example of a non-invasive route for rate-controlled peptide drug delivery and absorption enhancement, will be discussed.

II. Potentials and limitations of rectal peptide drug delivery

H.1. Physiology and histology of the rectal cavity The rectum represents an interesting body cavity for the administration of drugs. Its conditions with respect to pH (7.5-8), temperature (37 °C), humidity, volume of fluid ( ~ 3 ml), viscosity, etc., are quite constant [2-4]. Its surface area is quite small (200-400 c m 2) a n d the residence time of drugs in the rectum is only limited by defecation. Normally, the rectum is empty and flat while there is little peristaltic movement. Its pressure varies between 0 and 50 c m H 2 0 and is influenced by posture. The rectum has the capacity to neutralize acidic and

R A T E - C O N T R O L L E D RECTAL PEPTIDE D R U G ABSORPTION E N H A N C E M E N T

239

basic solutions by restoring the pH into the direction of pH 7-8 [5]. Histologically, the rectum comprises columnar epithelial cells without villi whereas in the anal canal this changes from cuboidal into stratified squamous epithelium at the proximal part. In addition there are numerous goblet cells in the rectum [6]

H.2. Venous drainage of the rectum The blood supply of the rectum is rich. It is drained by three veins: the upper, the middle and the lower rectal vein. The upper rectal vein is connected with the portal system while the middle and lower rectal veins are connected via the iliac veins with the inferior vena cava [6]. Therefore, drugs absorbed into the upper rectal vein will pass through the liver and will be subject to hepatic first-pass elimination, while drugs absorbed into the middle and lower rectal veins can be transported directly into the general circulation, thus escaping from hepatic first-pass elimination. This picture is complicated by the presence of anastomoses between these venes [6]. Therefore the site of drug delivery in the rectum and the direction of the blood flow in the rectal area determine the extent of hepatic first-pass elimination versus the amount of unchanged drug entering the general circulation. It has been shown, in man as well as in rats, that rectal administration of lidocaine close to the anus results in considerably higher plasma concentrations than when administered at sites further away from the anus [7-9]. 11.3. Lymphatic drainage of the rectum The lymphatic drainage of the rectum is quite extensive too [6,10]. This offers the interesting possibility to avoid hepatic first-pass elimination by so-called lymphotropic delivery of drugs. The size of the drug seems to be critical for this type of delivery: larger drugs are preferentially absorbed into the lymph because the fenestrae in the lymph vessels are larger than in the blood vessels [11,12]. Unfortunately, absorption enhancers are needed to obtain lymphotropic delivery of such large entities in particular if they are of a hydrophilic nature. It is also important to realize that the lymph flow in the rectum is much lower than the blood flow, which means that this route of administration is probably only important for very potent drugs or drugs whose action is mainly meant to be located in the lymphatic system draining the rectum. H.4. Bioavailability and transport routes of peptide drugs Drugs given rectally exhibit very often reduced bioavailability as compared to oral administration. As explained in subsection II.2 the reverse is often true for high-clearance drugs. However, formulation design is also of great importance, i.e., suppositories may be associated with absorption problems, because there is only a limited amount of water in the rectum. When administered in a (micro)enema drugs show often increased bioavailability and a more rapid absorption [2,4,13].

240

A.G. D E B O E R ET AL.

The absorption of peptides from the rectum and their appearance into the general circulation is hindered by physical [14] and metabolic barriers [15-17]. Fig. 1 schematically indicates the physical barriers to be overcome when peptides are absorbed via the paracellular or transcellular route [18]. Transport via the transcellular route requires that luminal mucus and stagnant water layers have to be passed and, subsequently, at least the apical membrane, the cytoplasm and the basolateral membrane. This may occur by: (a) passive lipophilic diffusion; (b) fluid-phase transcytosis or endocytosis followed by diffusion out of the cell; (c) receptor-mediated transcytosis. Since peptides are in general hydrophilic compounds, passive lipophilic diffusion is not expected to contribute much to their transmembrane transport. Fluid-phase transcytosis on the other hand comprises non-selective and also relatively slow transport. Therefore, receptor-mediated transcytosis seems to be the most potential transcellular transport process for peptides. However, it requires the availability of a suitable receptor which cycles between the apical and basolateral membrane. This implies that it is selective (specific) and may therefore only transport a limited class of peptides. In contrast to the transcellular route the paracellular route comprises PARACELLULAR

TRANSCELLULAR

LUMEN MUCUS TIGHT JUNCTION

LUMEN MUCUS GL YCOCALYX APICAL MEMBRANE CELL BODY BASOLA TERAL MEMBRANE

FLUID BASEMENT MEMBRANE

LYM.H

L,VER+

/

Fig. 1. Physical barriers presented by the para- and transcellular rectal route [18].

R A T E - C O N T R O L L E D RECTAL PEPTIDE D R U G ABSORPTION E N H A N C E M E N T

241

transport of drugs via the tight junctions and, subsequently, the interstitial space. It is therefore in principle a hydrophilic route and transport is mainly limited by the size and/or charge of the tight junctions. In addition, this nonselective route comprises less physical (Fig. 1) and metabolic barriers than the transcellular route and offers therefore interesting possibilities for peptide drug transport. It has been suggested that transport via the tight junctions is dynamically regulated "in response to physiological, pathological and experimental conditions" [19,20]. Therefore, the regulatory systems involved may provide opportunities to modify tight-junctional transport and to increase peptide absorption.

H.5. Metabolic degradation of peptides Metabolic barriers for peptides are ubiquitous in the rectum [14-17,21] starting with their pre-systemic elimination by peptidases in the rectal lumen or wall. Along the GI-tract this degradation process is site dependent because qualitative as well as quantitative differences have been detected [15]. In addition, regional differences exist with regard to peptidase activity in the brush border and the cytoplasm [22]. On the other hand, the degradation of peptides in the rectal lumen is probably much less than in the higher parts of the GI-tract. The activity of exoand endopeptidases, that are secreted into the gut lumen by the stomach and the pancreas, cleaving peptides at their N- and C-termini and at an internal peptide bond, respectively, is considerably lower in the rectum [15]. In addition it is known that the activity of dipeptidases in the wall of the human GI-tract is decreasing from duodenum to rectum [23]. This does not imply that the metabolic activity in the rectum is negligible. It was shown in rats that the metabolic breakdown of desenkephalin-~-endorphin and insulin can be inhibited by EDTA and aprotinin, respectively [24,25]. In addition, in rabbits there is an appreciable activity of aminopeptidases in the rectal wall which is in the same order of magnitude as in the nasal cavity, the buccal area and the duodenum [26]. An additional cause of metabolism is presented by micro-organisms in the rectal area. The amount of microorganisms is progressively increasing from jejunum to rectum [27], but it seems that their actions are mainly limited to ester hydrolysis or the reduction of azo-bonds [2,28-30]. Several methods have been proposed to circumvent the metabolic barriers, for example, by increasing the stability of peptides to peptidases or by inhibiting peptide metabolism [15,21,31,32]. The former methods comprise the chemical manipulation of the molecule in order to decrease the possibilities for attack by and sensitivity to peptidases while the latter methods comprise the application of metabolic inhibitors. However, such compounds may introduce an additional problem, since they may damage or disturb the mucosal integrity, thus limiting their applicability.

242

A.G. DE BOER ET AL.

H.6. Other factors influencing rectal peptide absorption It is known that various peptides present in the intestinal epithelium are able to influence the physiological functions of the gut [33]. This may imply that absorption processes, including that of peptides, are influenced too. It has been shown that in the rectum the concentrations of peptide YY, enteroglucagon and somatostatin, which are predominantly present in endocrine cells within the mucosa, are three times as high as in the colon, while the concentrations of vasoactive intestinal peptide and peptide histine methionine decrease towards the rectum [34]. Such regional differences also occur with respect to stomach and small intestine [35]. It has been suggested that "regional differences in colonic mucosal concentrations of regulatory peptides probably reflect differences in the physiological functions of different parts of the colon". Therefore it may be important to consider that transport processes in the rectum may be regulated differentially, in qualitative and/or quantitative way, as compared with higher parts of the GI-tract. This issue may have consequences for the manipulation of transport systems in order to increase peptide absorption. Age may also affect the activity or the concentrations of protein and peptides along the GI-tract [36]. Rectal concentrations of vasoactive intestinal peptide, substance P, neurokinin A but not peptide tyrosine tyrosine were shown to decrease with age, the former three peptides being mainly present in nerve fibres within the rectal mucosa. III. Rate-controlled rectal peptide delivery and absorption enhancement

III.1. Rate-controlled rectal drug delivery As discussed above, the conditions of the rectum are quite constant with respect to pH, temperature, amount and viscosity of fluid. Apart from strong bowel movements on defecation, there is little motility of the rectal walls. This provides the opportunity for administering and maintaining rate-controlled dosage forms in this body cavity for defined periods of time [37]. With 2 ml osmotic systems (OSMET), it was demonstrated for theophylline [38] and antipyrine [39] that the in vitro release rate and the in vivo absorption rate were the same when administered rectally to healthy subjects for 1 3 days. This makes it feasible, in principle, to predict the plasma concentration-time profile following rectal administration on the basis of in vitro release data and estimated i.v. kinetics. 111.2. Rate-controlled rectal peptide delivery and absorption enhancement The absorption of various peptide drugs on rectal administration has been investigated. They pass the rectal wall to a very variable extent, e.g., calcitonin [40,41], insulin [25,42-44], desenkephalin-[3-endorphin [24], desglycine arginine vasopressin [45], human fibroblast interferon (HuIFN[3) [46], pentagastrin and gastrin [47]. In general absorption enhancers are needed to achieve absorption, such as

R A T E - C O N T R O L L E D RECTAL PEPTIDE D R U G ABSORPTION E N H A N C E M E N T

243

fatty acids, sodium salicylate, mixed micelles and sodium tauro-24,25dihydrofusidate and several others (see Ref. 3). Rate-controlled rectal peptide drug delivery also requires the application of absorption enhancers. Fig. 2 shows the possible determinants of the resulting plasma concentrationtime profile of drugs following application together with an absorption enhancer. This indicates that it is relatively complicated to control or predict the plasma concentration-time profiles of peptide drugs, even when administered in a rate-controlled way. The following is an experimental example to illustrate this. The influence of the rate of administration of drug a n d / o r enhancer on the plasma concentration-time profile of the drug, is demonstrated by the rectal administration of cefoxitin to rats, with sodium salicylate as enhancer [48]. Bolus administration resulted in a larger area under the plasma concentrationtime curve than on infusion of the two compounds. However, when M G K (a commercially available mixture of glycerol, octanoic acid and glycerylmono-, di- and trioctanoate) was used with cefazolin [49], the enhancer was more effective when given together with the drug as an infusion. The results obtained in man are also difficult to explain because here the bioavailabilities following administration of cefoxitin together with sodium salicylate as a bolus or as an infusion were not different, while the application of sodium octanoate as enhancer resulted in a larger bioavailability when given as a bolus [50]. In addition the effect of the absorption enhancers in man was much lower than in rats: in man the maximal bioavailability of cefoxitin was 13% _+5% (S.D.) with ROUTE OF ADMINISTRA"nON

ABSORPTION OF DRUG RATE OF ABSORPTION EXTENT OF ABSORPTION

l

DRUG PLASMA CONCENTRATION PROFILE

Fig. 2. The various possible determinants of the plasma concentration-time profile of drugs on application together with absorption enhancers [18].

244

A.G. D E B O E R ET AL.

enhancer and 5.0%+_1.2% (S.D.) without enhancer while in rats these bioavailabilities were 100% and 8-32%; respectively. Similar results in rats were shown for the peptide desglycinamide arginine vasopressin, where rectal infusion together with 4% sodium tauro-24,25dihydrofusidate was more effective ( 4 2 % _ 12% S.D.) than when given as a bolus (27%_+6% S.D.) [45]. It should be mentioned, however, that 4% S T D H F is causing mucosal damage, as will be discussed later. The influence of the delivery rate on the extent of absorption as observed in these studies has tentatively been explained in terms of absorption rate of enhancer and of mucosal surface area that the solutions were exposed to [24]. The general conclusion is that rectal peptide absorption enhancement is quite feasible, but still little is known about the mechanism of action of enhancers, their concentration-effect relationship, the intra- and interspecies specificity and their safety [51].

111.3. The influence of the concentration-effect relationship of a n enhancer on the plasma concentration-time profile of a peptide drug Very little is known about the relationship between the concentration of an enhancer and its effect in terms of the profile and the area under the plasma concentration-time curve of a peptide drug. In order to control or predict the plasma concentration-time profile it is important to know this concentration-effect relationship, including its dependence on the rate and route of administration. An example in rats is given in Fig. 3. It shows that for sodium tauro-24,25-dihydro-fusidate there is an optimum concentration regarding its maximal effect on A U C of desglycinamide arginine vasopressin [45]. Similar results have been observed for cefoxitin with fatty acids as absorption enhancers [52]. It should be noted AUC(0-infinity) following RECTAL

of DGAVP administration

10 E

8

- ~- rectal infusion

rE

6

- o- rectal bolus

T

4 (J <

-A-

i,v.

2 ,,/' 0 1 %

3 STDHF

5

7

9

(w/v)

Fig. 3. Mean AUC's (0-o@ + S.D. of DGAVP after i.v. infusion and after simultaneous rectal administration of 30 lag of DGAVP as an infusion ( + - + ) and as a bolus ( O - O ) with various concentrations of STDHF [45].

R A T E - C O N T R O L L E D RECTAL PEPTIDE D R U G ABSORPTION E N H A N C E M E N T

245

that large variations are seen in the results following application of absorption enhancers, which may be due to intra- and interindividual differences with i'espect to these concentration-effect relationships and absorption rates of enhancers. An attempt (de Boer, A.G., van Hoogdalem, E.J. and Breimer, D.D., unpublished results) has been made to simulate these effects for a poorly absorbed drug whose i.v. kinetics can be described by a one-compartment model with a ke value of 0.15 h -1. It is assumed that the site of the effect is located at the apical membrane of the rectal epithelium and that the absorption rate constant of the enhancer (kac) is not changed by its absorption-enhancing effect. The concentration of the enhancer at the apical membrane in the rectal lumen (Cle) is therefore the important factor for its absorption enhancing effect. This concentration will change when the enhancer is absorbed. It is assumed that the absorption rate of the enhancer is first-order and that at t = 0, the concentration of the enhancer at the apical membrane is 6 ~tg/ml (Cle,max). The solutions with and without enhancer are given as a bolus administration.

SIGMOID MODEL 0.005 (l/h)

kad: 12.50 ]

10.OO 1 7.50

]

5,00 t tO

0

50

100

150

TIME (h) SIGMOID MODEL 0.005 (l/h)

kad: 1.00 0.75 0.50 LL

0.25 0.00 50

100

150

TIME (h)

Fig. 4. a: simulated plasma concentration-time profile following rectal administration (bolus) of a poorly absorbed drug (cefoxitin) without enhancer. The first-order absorption rate is 0.005 h t. b: the dependence of bioavailability on time for the simulation shown in a.

246

A.G. DE BOER

ET AL.

The effect of the enhancer may be related to the first-order absorption rate of the poorly absorbed drug by a sigmoidal relationship:

kad =

kad,max × Cle g

+ 0.005

Cle,50 g + Cle g

where the maximal first-order absorption rate constant of the drug,kad,max , = 1 h - l ; kad (in h-1), is the resulting first-order absorption rate constant; Cle,50 is the concentration of the enhancer in the rectal lumen when the effect (kad) is 50% of kad,max; and the shape parameter g = 1. When no enhancer is applied the absorption rate constant is 0.005 h - l ; however, with enhancer kad may vary between 0.005 and 1.005 h 1. Fig. 4a shows the plasma concentration-time profile when the drug is given rectally as a bolus without enhancer. In this situation the basal first-order absorption rate is 0.005 h-1. In this situation bioavailability (Fig. 4b) is very much dependent on the residence time of the drug in the rectal area. Fig. 5a shows the simulation when the drug is given together with an absorption enhancer. It shows that all plasma concentration-time profiles are almost superimposable when Cle,50 = 1 ~tg/ml and kae is varied from 0.0001 to 0.5001 h - l . This means the enhancer is relatively potent which gives rise to maximal bioavailability (see Fig. 6a) in the kae-range studied. However, when a SIGMOID M O D E L kae: changing, Cle,50: 1 ug/ml - - 0.0001 12.50 ....

0.1001

---

0,2001

....

0.3001

---"

0.4001

10.00 .~

7.50

~.

5.00

0

2.50

\

0.00

. . . . . 100 150

50 TIME

.~

(h)

SIGMOID M O D E L kae: changing, C l e , 5 0 : 6 4

ug/mol.ooo 1

12.501

---

O.lOOl

---

0,2001

10.00 7.50 5.00

'O

0,5001

2.50 0.00

t ~

/

x

...... o . 3 o o l

~

~ 0

50 TIME

100

---

0.4001

--'"

0.5001

150

(h)

Fig. 5. a: simulated plasma concentration-time profiles following rectal administration (bolus) of a poorly absorbed drug (cefoxitin) together with enhancer. The absorption rate of the enhancer is varied from 0.0001 to 0.5001 h - ] in steps of 0.1000 when C~e,5o= 1 gg/ml. Cpd is the plasma concentration of the absorbed drug. b: the same simulation as in a but when Clc,5o = 64 gg/ml.

RATE-CONTROLLED RECTAL PEPTIDE DRUG ABSORPTION ENHANCEMENT

247

less potent absorption enhancer (Cle,5 0 = 64 gg/ml) is applied and the s a m e kaerange is simulated, the picture becomes quite different. Fig. 5b shows that peak concentrations are reduced considerably and that flip-flop kinetics occur. In addition, bioavailability (see Fig. 6b) is now very much dependent on the absorption rate of the enhancer. It may be concluded, therefore, that for potent absorption enhancers the absorption rate of the enhancer does not seem to be very important when the drug is given together with the enhancer as a bolus. Fig. 7a shows that in the time interval of absorption enhancement kad is sufficiently large to be able to reach maximum bioavailability. Application of less potent absorption enhancers implies that the relative potency (in terms of Cje,5O) and the absorption rate of the enhancer, which is much less (see Fig. 7b) have a considerable influence on the plasma concentration-time profile of a drug following simultaneous bolus administration. These simulations indicate that it is important to know the concentrationeffect relationship of the enhancer and also the i.v. kinetics of the drug in order to be able to optimize the input that leads, theoretically at least, to the desired plasma concentration-time profile of the peptide.

IV. Limitations of rectal absorption enhancement Various limitations exist when rectal absorption of peptide drugs is to be enhanced. These include the existence of physical and metabolic barriers, the effect of the rate of administration of the enhancer and the relationship between the concentration of the enhancer and its effect in terms of the profile and the area under the curve of the peptide drug. Furthermore, data about the safety of absorption enhancers are scarce. It is obvious that the acceptability of enhancers must be considered in the light of efficacy versus safety. Both are likely to be dependent on frequency and time period of administration, the route of administration, the concentrations of drug and enhancer used. This is probably different from enhancer to enhancer (e.g., with respect to absorption rate or residence time, potency and mechanism of action). An attempt has been made to score (histologically and macroscopically) the effects of enhancers on the rectal mucosa of rats [51]. The results obtained indicate that when a detailed scoring procedure is applied, a distinction can be made between the various enhancers with respect to their potentially harmful effect(s) and the time needed for the mucosa to recover. For instance, in rats the effects of cefoxitin plus sodium salicylate (6%) and Azone (1%), are histologically moderate and comparable after 2 and 24 h following bolus administration, while monoglycerides and sodium salts of fatty acids are initially quite harmful and show a slight recovery after 24 h. The effect of the concentration on the extent of mucosal damage was demonstrated with STDHF. Cefoxitin plus 0.5% S T D H F causes moderate changes after 2 h, but shows almost complete recovery after 24 h. A concentration of 4% STDHF,

248

A . G . D E B O E R ET AL. SIGMOID MODEL kae: changing, Cle,50: 1 ug/ml - - o.oool 1.00 i f

= = ' ' ~ ~

__. O.lOOl

0.75 ~

---

o.2ool

.c

0.50

o.3ool

LL

0.25

--++ 0.4001

0.00 0

50

100

.... 150

o.5ool

TIME (h) SIGMOID MODEL kae: changing, Cle,50: 64 1.00 ]

ug/ml - - o.oool

~-

. . . . 0.1001

0.75

-o.2ool

0.50

"~J" ,'' / / ~ ~ ..-~"~

o.3ool

0.25

- - - . 0.4001

0.00 0

50

100

---- 0.5o01 150

TIME (h)

Fig. 6. a:bioavailabilities of the simulation shown in Fig. 5a when Clc,50= 1 lag/ml, b: bioavailabilities of the simulation shown in Fig. 5a when CIc,5o= 64 ~g/ml.

SIGMOID MODEL kae: changing, Cle,50: 1 ug/ml -

1.00 ~

-

o.oool

. . . . O.lOOl

0.80 0.60

'i",~1',

---

0 . 4 0 11~ ",

o.2ool 0.3001

0.20

---" 0.4001 \

0.00 0

. . 50

. . . . 100 150

o.5ooi

TIME (h) SIGMOID MODEL kae: changing, Cle,50: 64

.c

ug/rnl - - o.oool

[

1.00 ] 0.80 0.60 0.40 0.20

. . . . O.lOOl - - - 0.2001 .... o.3o01 - - - o.4o01

0 . 0 0 "~'~'0 50

---- o.5ool 150 •

100

TIME (h)

Fig. 7. a: absorption rate constants for the simulations shown in Fig. 5a. b: absorption rate constants for the simulations shown in Fig. 5b.

RATE-CONTROLLED RECTAL PEPTIDE DRUG ABSORPTION ENHANCEMENT

249

however, shows almost no recovery after 24 h. These data stress the need for a careful histological examination of the mucosal effects of enhancers in relation to their concentration, their frequency of administration and the recovery time of the mucosal cells. References 1 Breimer, D.D. (1989) Pharmaco-Biotechnology, Biotechnology and the Pharmaceutical Industry, Annual Report Gist-Brocades NV, Delft, The Netherlands. 2 De Boer, A.G., Moolenaar, F., De Leede, L.G.J. and Breimer, D.D. (1982) Rectal drug administration: clinical pharmacokinetic considerations, Clin. Pharmacokinet. 7, 285-311. 3 Van Hoogdalem, E.J., De Boer, A.G. and Breimer, D.D. (1989) Intestinal drug absorption enhancement. An overview, Pharmacol. Ther. 44, 407-443. 4 De Blaey, C.J. and Polderman; J. (1980) Rationals in the design of rectal and vaginal delivery forms of drugs. In: Ariens (Ed.), Drug Design, Vol. 9, Academic Press, London. 5 Crommelin, DJ.A., Modderkolk, J. and De Blaey, C.J. (1979) The pH dependence of rectal absorption of theophylline from solutions of aminophylline in situ in rats, Int. J. Pharmaceut. 3, 299 309. 6 Netter, F.. In: The Ciba Collection of Medical Illustrations, Vol. 3, Digestive Systems, Part II, pp. 72 73. 7 De Boer, A.G., Breimer, D.D., Mattie, H., Pronk, J. and Gubbens-Stibbe, J.M. (1979) Rectal bioavailability of lidocaine in man: partial avoidance of first-pass metabolism, Clin. Pharmacol. Ther. 26, 701 709. 8 De Leede, L.G.J., De Boer, A.G., Roozen, C.P.J.M. and Breimer,D.D. (1983) Avoidance of first-pass elimination of rectally administered lidocaine in relation to the site of absorption in rats, J. Pharmacol. Exp. Ther. 225, 181-185. 9 De Leede, L.G.J., De Boer, A.G., Feijen, C.D. and Breimer, D.D. (1984) Site-specific rectal drug administration in man with an osmotic system: influence on first-pass elimination of lidocaine, Pharm. Res. 1, 129-135. 10 T6ndury, G. (1959) Angewandte und Topographische Anatomie, George-Thieme-Verlag, Stuttgart. 11 Caldwell, L., Nishihata, T., Rytting, J.H. and Higuchi, T. (1982) Lymphatic uptake of watersoluble drugs after rectal administration, J. Pharm. Pharmacol. 34, 520-522. 12 Yoshikawa, H., Muranishi, S. and Sezaki, H. (1983) Mechanisms for selective transfer of bleomycin into lymphatics by a bifunctional delivery system via the lumen of the large intestine, Int. J. Pharm. 13, 321 332. 13 Van Hoogdalem, E.J., De Boer, A.G. and Breimer, D.D. (1991) Rectal drug therapy; pharmacokinetics and clinical applications, Clin. Pharmacokinet., in press. 14 Gardner, M.L.G. (1988) Gastrointestinal absorption of intact proteins, Annu. Rev. Nutr. 8, 329-50. 15 Lee, V.H.L. (1988) Enzymatic barriers to peptide and protein absorption, Crit. Rev. Ther. Drug Carrier Syst. 5, 69-97. 16 Adibi, S.A. and Kim, Y.S. (1981) Peptide absorption and hydrolysis. In: L.R. Johnson (Ed.), Physiology of the Gastrointestinal Tract, Raven Press, New York, pp.1073-95. 17 Alpers, D.H. (1986) Uptake and fate of absorbed amino acids and peptides in the mammalian intestine, Fed. Proc. 45, 2261-2267. 18 De Boer, A.G., Van Hoogdalem, E.J., Heijligers-Feijen, C.D., Verhoef, J.C. and Breimer, D.D. (1990) Rectal Absorption Enhancement of Peptide Drugs, J. Controlled Release 13, 241 246. 19 Madara, J.L. (1988) Tight junction dynamics: is paracellular transport regulated?, Cell 53, 497498. 20 Cereijido, M., Gon~'lez-Mariscal, L., ,~.vila, G. and Contreras, R.G. (1988) Tight Junctions, CRC Crit. Rev. Anatom. Sci. 1, 171 192.

250

A.G. DE BOER ET AL.

21 Barret, A.J. (1977) Proteinases in mammalian cells and tissues. In: J.T. Dingle (Ed.), Research monographs in cell and tissue physiology, Vol. 2, Elsevier/North-Holland, Amsterdam. 22 Kim, Y.S., Kim, Y.W. and Sleisenger, M.H. (1974) Studies on the properties of peptide hydrolases in the brush border and soluble fractions of small intestinal mucosa of rat and man, Biochim. Biophys. Acta 370, 283 296. 23 Lindberg, T. (1966) Intestinal dipeptidases: dipeptidase activity in the mucosa of the gastrointestinal tract of the adult human, Acta Physiol. Scand. 66, 437. 24 Van Hoogdalem, E.J., Heijligers-Feijen, C.D., De Boer A.G. and Breimer, D.D. (1989) Rectal absorption enhancement of desenkephalin-13-endorphin (DEYE) by medium-chain glycerides and EDTA in conscious rats, Pharm. Res. 6, 91-5. 25 Nishihata, T., Liversidge, G.G. and Higuchi, T. (1983) Effect of aprotinin on the rectal delivery of insulin, J. Pharm. Pharmacol. 35, 616-617. 26 Stratford, R.E. and Lee, V.H.L. (1986) Aminopeptidase activity in homogenates of various absorptive mucosae in the albino rabbit: implications in peptide delivery, Int. J. Pharm. 30, 7382. 27 Broitman, S.A. and Gianella, R.A. (1971) In: Rabinowitz and Myerson (Eds.), Topics in Medicinal Chemistry: Absorption Phenomena, Wiley Interscience, New York, Vol. 4, pp. 265321. 28 Scheline, R.R. (1973) Metabolism of foreign compounds by gastro-intestinal microorganisms, Pharmacol. Rev. 25, 451 523. 29 Goldman, P. (1978) Biochemical pharmacology of the intestinal flora, Annu. Rev. Pharmacol. Toxicol. 18, 523 539. 30 Boxenbaum, H.G., Bekersky, I., Jack, M.L. and Kaplan, S.A. (1979) Influence of gut microflora on bioavailability, Drug Metab. Rev. 9, 259-279. 31 Wyvratt, M.J. and Patchett, A.A. (1985) Recent developments in the design of angiotensinconverting enzyme inhibitors, Med. Res. Rev. 5, 483. 32 Samanen, J.M. (1985) Polypeptides as drugs. In: C.G. Gebelein and C.E. Carraher (Eds.), Polymeric Materials in Medication, Plenum Press, New York, pp. 227. 33 Laburthe, M. (1990) Peptide YY and neuropeptide Y in the gut, availability, biological actions and receptors, TEM (January/February),168-174. 34 Calam, J., Ghatei, M.A., Domin, J., Adrian, T.E., Myszor, M., Gupta, S., Tait, C. and Bloom, S.R. (1989) Regional differences in concentrations of regulatory peptides in human colon mucosal biopsy, Dig. Dis. Sci. 34, 1193 1198. 35 Bloom, S.R. and Polak, J.M. (Eds.) (1981) Gut Hormones, 2nd edn., Churchill Livingstone, Edinburgh. 36 Donckier, J., McGregor, G.P., Impallomeni, M., Calam, J. and Bloom, S.R. (1987) Age-related changes in regulatory peptides in rectal mucosa, Acta Gastroenterol. Belg. L, 405-410. 37 Breimer, D.D., De Boer, A.G. and De Leede, L.G.J. (1985) Rate-controlled rectal drug delivery, J. Controlled Release 2, 39-46. 38 De Leede, L.G.J., De Boer, A.G., Van Velzen, S.L. and Breimer, D.D. (1982) Zero-order rectal delivery of theophylline in man with an osmotic system, J. Pharmacokin. Biopharm. 10, 525 537. 39 De Leede, L.G.J., De Boer, A.G. and Breimer, D.D. (1981) Rectal infusion of the model drug antipyrine with an osmotic delivery system, Biopharm. Drug. Dispos. 2, 131 136. 40 Buclin, T., Randin, J.P., Jacquet, A.F., Azria, M., Attinger, M., G6mez, F. and Burckhardt, P. (1987) The effect of rectal and nasal administration of salmon calcitonin in normal subjects, Calcif. Tissue Int. 41,252-258. 41 Morimoto, K., Iwamoto, T. and Katsuaki, M. (1987) Possible mechanisms for the enhancement of rectal absorption of hydrophilic drugs and polypeptides by aqueous polyacrylic acid gel, J. Pharmacobiodyn. 10, 85-91. 42 Van Hoogdalem, E.J., Heijligers-Feijen, C.D., Verhoef, J.C., De Boer, A.G. and Breimer, D.D. (1990) Absorption enhancement of rectally infused insulin by sodium tauro-24, 25dihydrofusidate (STDHF) in rats, Pharm. Res. 7, 180-183. 43 Epstein, D.A. and Longenecker, J.P. (1988) Alternative delivery systems for peptides and proteins as drugs, Crit. Rev. Ther. Drug Carrier Syst. 5, 99-139.

RATE-CONTROLLED RECTAL PEPTIDE DRUG ABSORPTION ENHANCEMENT

251

44 Touitou, E. and Donbrov, M. (1983) Promoted rectal absorption of insulin: formulative parameters involved in the absorption from hydrophilic bases, Int. J. Pharm. 15, 13-24. 45 Van Hoogdalem, E.J., Heijligers-Feijen, C.D., Math6t, R.A.A., Wackwitz, A.T.E., Van Bree, J.B.M.M., Verhoef, J.C., De Boer, A.G. and Breimer, D.D. (1989) Rectal absorption enhancement of cefoxitin and desglycinamide arginine vasopressin (DGAVP) by sodium tauro-24,25-dihydrofusidate (STDHF) in conscious rats, J. Pharmacol. Exp. Ther. 251,741-744. 46 Yoshikawa, H., Takada, K., Muranishi, S., Satoh, Y. and Naruse, N., (1984) A method to potentiate enteral absorption of interferon and selective delivery into lymphatics, J. Pharmacobiodyn. 7, 59-62. 47 Yoshioka, S., Caldwell, L. and Higuchi, T. (1982) Enhanced rectal bioavailability of polypeptides using sodium 5-methoxysalicylate as an absorption promoter, J. Pharm. Sci. 71, 593-594. 48 Van Hoogdalem, E.J., Van Kan, H.J.M., De Boer, A.G. and Breimer, D.D. (1988) Ratecontrolled absorption enhancement of rectally administered cefoxitin in rats by salicylate, J. Controlled Release 7, 53-60. 49 Van Hoogdalem, E.J., Stijnen, A.M., De Boer, A.G. and Breimer, D.D. (1988) Rate-controlled absorption enhancement of rectally administered cefazolin in rats by a glyceride mixture (MGK), J. Pharm. Pharmacol., 40, 329-332. 50 Van Hoogdalem, E.J., Wackwitz, A.T.E., De Boer, A.G., Cohen, A.F. and Breimer, D.D. (1989) Rate-controlled rectal absorption enhancement of cefoxitin sodium salicylate and sodium octanoate in healthy volunteers, Br. J. Clin. Pharmacol. 27, 75-81. 51 Van Hoogdalem, E.J., Vermey-Keers, C., De Boer, A.G. and Breimer, D.D. (1990) Topical effects of absorption enhancing agents on the rectal mucosa of rats in vivo, J. Pharm. Sci. 79, 866-870. 52 Van Hoogdalem, E.J., Hardens, M.A., De Boer, A.G. and Breimer, D.D. (1988) Absorption enhancement of rectally infused cefoxitin sodium by medium-chain fatty acids in conscious rats: concentration-effect relationship, Pharm. Res. 5, 453456.