Physiology of the colorectal barrier

advanced

drug delivery reviews

ELSEVTER

Advanced Drug Delivery

Physiology

Reviews 2X ( 1997)

173-190

of the colorectal barrier Christine

Edwards

’

Abstract The colon is a suitable site for the safe and slow absorption of drugs which are targetted at the large intestine or designed to act sytemically. The physiology of the colorectal barrier is complex and influenced by many factors including diet, bacterial metabolism and colonic mixing and transit time. As the motility and absorption characteristics of the colon change from the proximal colon to the rectum, the physiology of these regions and the likely residence time of any drug at each site must be understood for the full potential of the colon to be exploited. This article will discuss the main physiological factors 0 1997 Elaevier Science B.V. affecting the colon and hence colonic drug absorption. Kqwwtds:

Colonic physiology:

Barriers to absorption:

&Ionic

motility; Colonic absorption:

Bacterial metabolism

Contents Introduction ............................................................................................................................................................................

174

Functional sites in the colon.. ...................................................................................................................................................

174

3. I. Colonic neural supply.. ..................................................................................................................................................... 7.2. Blood supply and circulation .............................................................................................................................................

I75

2.3. Mucoaal structure.. ...........................................................................................................................................................

176

Absorption mechanisms in proximal and distal colon .................................................................................................................

176

3. I.

Electrolytetransport

3.2. Absorption

mechanisms

176

...................................................................................................................................... I76

of water .........................................................................................................................................................

177

3.3. Absorption of other molecules including drugs ...................................................................................................................

177

3.4. Ahwrption

I78 I78

of short-chain fatty acids .................................................................................................................................

Rarrier~ 10 ahsorption

4.I. Mucosaland

............................................................................................................................................... .....

physical harriers.. .........................................................................................................................................

I78

4. I. I. Mucus layer.. ......................................................................................................................................................... 3. I .?. Unstirred water layer.. ..............

.....

I78

.................... ...... ................ ................................ ........ ...... ...... ........

179

4.3. Chemical barrlcrs .............................................................................................................................................................

179

4 4. Microbiological

1.4.I.

harriers

..............................................

5.I.

..............

.......

...................

... .........

......

Indirect action of fermentation ................................................................................................................................

Colomc motility, transit time and colonic residence. Colonic muscles. ..................................

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fax:

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e-mail:

1997 Elsevier Science B.V. All rights Ireserved

97 )0007

I-9

179 IX0

.................................................................................................................. I80

5.2. Colonic motor patterns ..................................................................................................................................................... 5.2. I. Measurclnent of colonic motility ............................................................................................................................. 5.2.2. Electrical bask of motility ............................................. ... ....................................................................

P/I

I79

4.2. Bulk phase mixing and entrapment.. ..................................................................................................................................

I80 IX0 I81 1x1

5.3. Factors affecting contractile actlwty

..........

.._.... .._...

5.4. Stimulation of colonic motility .,..

5.5. Transit h.

time and residence ..,

.._. .._.....

Factors affecting transit time ,.....,,,,,,...,.....,,,,........................................................................................................................... 6. I, Transit time of pharmaceutical dosage forms through the intestme

.._...._...

7. Conclusions and areas of uncertuinty Reference\

..,...

,,,,..

.._.._......._..._.....

IX4

..__... .._.___.. 184

.._..................................................

.._.....

1. Introduction For many years the human colon was regarded as an unnecessary organ which absorbed water and electrolytes. In the last few decades, however, the colon has been identified as a organ of importance for the nutrition and health of man having a large metabolic activity, by proxy of its intestinal microflora, and a significant ability to absorb a wide range of compounds. Although the human colon has a lower absorption capacity than that of the small intestine, (the colonic surface area is only 0.3 m’ in comparison with the 120 m2 of the small intestine), material remains in the colon for much longer. Colonic residence time is 2-3 days, whereas food is in the small intestine for as little as 5 h ]I]. This long colonic residence time provides a significant opportunity for the slow absorption of drugs and other materials, either targetted specifically at the large intestinal mucosa or designed to act systemically. In addition, drugs which would be unstable in the small intestine may be released in the colon safely and absorbed there to act systemically. Drugs may be delivered to the colon orally in slow release or targeted forms 121, or rectally by enema [3] or suppository. Either way the drugs must overcome anatomical, physical, chemical and microbiological barriers to absorption present at each of the functional sites in the colon. In addition to the physical barriers of the colonic mucus, unstirred layer and the mucosal wall, drugs must also survive metabolic transformation by the abundant colonic bacterial flora and other chemical and physical interactions with luminal contents. The colonic flora is composed of up to 400 bacterial species (mainly obligate anaerobes) which possess a wide range of enzymic activities, including pglucuronidase, and P-glycosidase, capable of transforming a wide range of xenobiotics. The bacterial fermentation of carbohydrate may also influence

182

.._.... .._.._....._..... .._...... .._..._...._..............182 .._... .._..... .._....__.....____.... IX?

IX5

IX6

drug absorption indirectly by acidifying colonic contents and changing the luminal environment. Dietary components, such as complex carbohydrates with large water holding capacity, may dilute drug concentrations or trap molecules within a viscous network of polysaccharide chains. Colonic motor patterns are also important infuences on colonic drug absorption as they determine not only the rate of delivery to the absorptive sites but also residence time and the extent of mixing. The absorption characteristics and mechanisms of the colon differ from those of the small intestine, and those of the mucosa in the proximal colon differ from the characteristics and mechanisms of the distal colon. This along with the differences in the luminal contents and motility patterns in each area of the colon results in a variation of the properties of the colorectal barrier to drug absorption as the colon is traversed. In this review the properties of, and the factors affecting, each of these barriers will be discussed in relation to drug absorption.

2. Functional

sites in the colon

The human colon should not be considered as one functional unit. The proximal and distal colon differ in many properties (Fig. 1). There are differences in the anatomy, neural and blood supply and absorption characteristics as the length of the colon is traversed. The motility patterns, residence time and properties of luminal contents also differ. All of these will affect drug absorption and thus should be taken into account when designing drug delivery systems. In terms of size and complexity, the human colon falls between that of carnivores such as the ferret, which has no identifiable junction between ileum and colon, and herbivores such as the rat which have a voluminous cecum [4]. The human cecum is small and there is a rudimentary appendix.

C. Edwards I Advanced Drug Delivr~

I

Proximal colon

175

Rrriews 28 (1997) 17-T-190

Distal colon

I

Stora e Absorp FIon

Fermentation chamber Absorption -Spla%%?&bar

Innervation \

Pelvic/ lumbar

A YYB’ood

Superior mysenteric /

s”pp’y t

inferior mysenteric

Absorptive mechanisms Greater capacity chorld~~~~~~~~~~~~~pc~

95% chloride dependent Na transport electroneutral

Liquid

jll

Luminal characteristics_I[

,ss

b~~~~,i.i~y

pH 5-7 higher SCFA active bacterial metabolis

amino acid fermentation

carbohydrate fermentation

methane production

H2 production

I. Characteristics

Fig.

The three

human

colon

functional

can be divided

site

into

areas

The cecum and proximal main

arbitrarily

of the proximal

of bacterial

and therefore The transverse

colon.

carbohydrate

act as fermentation colon.

These

form

the

metabolism chamber.

Here the predominant

motor

colon for further fermentation or propel it distally, emptying the proximal colon. The transverse colon may also be an important site for the absorption of water and the formation of faeces. The distal colon and rectum. These act as a reservoir for fecal material allowing defecation to be delayed until socially convenient. patterns

hold

material

in the proximal

For most of this article the properties and roles of the proximal and distal colon will be considered. In addition to the site along the colon, there are also variations in the properties of different phases of colonic contents. The pH, dilution, viscosity and potential binding sites will depend on whether the drug is in the bulk phase or next to the mucosa, and whether it is free in the aqueous phase or bound to,

and distal colon

or trapped residues.

in, solid material

such as dietary

fibre

2.1. Colonic neurul suppl) The neural control of the colon changes from proximal to distal sites. The colon is supplied with both sympathetic and parasympathetic nerves but the sympathetic nerves dominate, maintaining a tonic inhibition of colonic motor activity [S]. The parasympathetic supply originates from both the vagus and the pelvic nerves. The vagus supplies the proximal and up to the mid-point of the transverse colon, whereas the pelvic or sacral spinal nerves innervate the entire colon 161. Parasympathetic stimulation causes an increase in contractility. The prpximal colon, however, contracts rhythmically, whereas the distal colon undergoes tonic contraction and shortening [5]. The sympathetic supply is from the postganglionic neurons, from the inferior mesenteric ganglion which arises from lumbar preganglionic outflow. There is also input from the splanchnic system. The splanchnit system influences the proximal colon, whereas the lumbar system influences the whole colon.

Electrical stimulation of the sympathetic nerves decreases the effects of parasympathetic stimulation and inhibits spontaneous motility. In addition to the autonomic nervous system. there is a complex enteric nervous system consisting of two major plexi. myenteric and subni~~cosal. and other small plexi in the n~ucosal and muscle layers. Each plexus contains organiaed networks 01‘ ganglia which process signals between cells in the same plexus. other plexi. extrinsic nerves and the muscle and mucosal layers playing a major role in the control of motility and transport processes. In the proximal colon the myenteric plex~~s i\ regular and ctellate. whereas the distal colon has a unique pattern of shunt fascicles [ 71 (large ner\:e bundles running along the axis of the colon) which connect with the ganglia and originate from the pelvic nerve [XI. The neural plexus in the rectum has an irregular appearance [ 7 I. The distal colon is more \ensiti\e to neural stimulation than the proximal colon having enhanced cholinergic activation and increased muscle sensitivity to acetylcholine 191. The neural control of the colon is reviewed in detail elsewhere [ 101.

The rate of absorption of drugs from the colon is influenced by the rate of blood flow to and from the absorptive epithelium. The arterial blood s~~pply to the proximal colon is from the superior mesenteric artery. The inferior mesenteric artery supplies the distal colon. Venous drainage is via the superior (proximal colon) and inferior (distal colon) veins. Measurement of blood flow to the colon is difficult. and reported preprandial blood flow values range from X to 75 ml/min [I 11. The proximal colon receives a greater share of the blood flow than more distal parts [ 121. although total colonic blood flow is less than that of the small intestine [I I]. Factors which increase blood flow include mechanical mucosal stimulation [ 131 and short-chain fatty acids [ 14,151. Sympathetic neural stimulation decreases blood flow and parasympathetic stimulation increases it [ I I I. Ingestion of food decreases blood flow 30-45 min after the meal [ I I]. When the colonic muscle contracts there is an overall increase in blood ilow to the colon to meet the demand of the contracting

muscle but mucosal capillaries may be constricted by the contraction and local blood flow reduced [ 161.

The absorptive capacity of the colon is much less than that of the small intestine and this is due mainly to a lower surface area. The mucosal surface of the colon at birth is similar to that of the small intestine but rapidly changes with the loss of the villi leaving ;I flat mucosa with deep crypts [ 171. As the gut ages there is a decrease in the number of non-goblet crypt cells and this is related to an increase in faecal water 1I Xl. The turnover of colonic enterocytes decreases from proximal to distal colon and rectum 1191, and colonic crypts in the distal colon are longer than those in the proximal colon 1201. Despite the lowel surface area. the colon has a large capacity for the absorption of water, electrolytes and the short-chain t’atty acids (SCFA) which are formed during fermentation of’ carbohydrate by the colonic bacteria. Of about IS00 ml water entering the colon, only 200 ml per day ih excreted. The colon is capable of absorbing -i I of water per day and can withstand an infusion rate of 6 ml/min before there is any increase in fecal water 12 1,331. The mechanisms by which some molecules are absorbed differ between proximal and distal colon and the rate of absorption is likely to decrease as material moves along the colonic lumen. This makes the residence time in a particular zone an important factor determining the rate of drug absorption.

3. Absorption distal colon

mechanisms

in proximal

and

The human colon absorbs sodium and chloride and secretes bicarbonate and potassium against electrochemical gradients. Sodium absorption and potassium secretion are increased by aldosterone. All regions of the colon actively absorb sodium and chloride at more or less similar rates when studied in vitro 12.31. In vivo perfusion and dialysis studies in man, however, indicate a greater absorption in the proximal and transverse colon 124-261. In the human, 50%

of active sodium transport is chloride dependent 1231. This differs from rat colon where active sodium transport is 80% dependent on chloride [27,28]. The mechanism of absorption differs with site. Electrogenic sodium transport (blocked by amiloride) increases from proximal to distal colon (23,281. In the proximal colon it is a minor pathway. about 8% of total sodium absorption 1291, but in the distal colon it accounts for 50- 100% of the sodium transport [ 23,301. The other major pathway is electrically neutral and coupled with chloride transport, most likely a parallel sodium-hydrogen, chloridebicarbonate exchange [30-321. There is a third active transport pathway that is not chloride dependent and not blocked by amiloride 1231, but which may be inhibited by phenamil, an amiloride analogue with high selectivity for the Nat channel [32] This is responsible for 7-15% of the transport in the distal colon and approximately 50% in the proximal colon. Potassium transport also differs in the proximal and distal colon. In vitro, the proximal colon seems to secrete potassium, whereas the distal colon absorbs potassium under basal conditions [33]. Aldosterone-treated tissue however, secretes potassium from both sites [331. Furthermore, in the presence of SCFA, the rabbit proximal colon absorbed potassium [ 331, emphasising the need to consider physiological conditions before interpreting the results of in vitro models that may not reflect the true in vivo environment. Potassium secretion in both the proximal and distal colon is an active process driven by the ouabain-sensitive Nat/K+ ATPase on the basolateral membrane. In vitro studies of rabbit colon [34] showed that when chloride was removed from the bathing solution in the distal colon, serosal to mucosal K’ flux was reduced increasing mucosal to serosal tlux and resulting in K’ absorption. Removing the chloride had no effect in the proximal colon. The mechanism is unknown but again emphasises the segmental heterogeneity of the proximal and distal colon. Potassium absorption is electroneutral by a paracellular 13.51 or transcellular route [36] mediated by a K ’ /H+ exchange across the apical membrane [37-391, and driven by a K’ ATPase on the apical membrane [40]. The absorption and secretion of K _ is further complicated by a low potassium concentration in the juxtamucosal microclimate,

which is more stable in the proximal colon than the distal colon [41,42]. This difference may relate to a higher transcellular route of potassium transport in the distal colon. The absorption of electrolytes is under the influence of the mucosal plexi 143.441. J.2. Absorption

of water

The colon is a major site of water absorption. Liquid effluent from the terminal ileum is transformed into a semisolid stool with approximately 60-85% water 1451. The main sites of water absorp tion are the proximal and transverse colon but absorption may be delayed by the presence of slowly fermentable dietary tibres of high water-holding capacity, such as ispaghula, xanthan or gellan [46,47] which results in more liquid content in the distal colon and increased stool output. Water retained in the colonic lumen may dilute the drug concentration-reducing rate of absorption but may also facilitate movement and mixing within the lumen to allow better contact with the epithelial surface. Water absorption occurs secondary to the absorption of electrolytes and SCFA by solvent drag. The colonic epithelium is less permeable than the small intestine and allows the water to be extracted against large transepithelial osmotic gradients. Studies in the rat have demonstrated hypertonic absorption across the crypts of the distal colon where an osmotic pressure equivalent to 5 atmospheres would be required to dehydrate the feces 1481. Perfusion studies in the rat rectum 1491 suggest that increasing water absorption with sodium taurocholate or EDTA-Na increased antipyrine absorption. This effect was significantly reduced by oubain, suggesting increased solvent drag by Na’ absorption as the promotional mechanism. .1..3. Absorption

qf other

moleculc~s including

drugs

Sugars such as glucose and sucrose [SO] and amino acids [5 1] are poorly absorbed in the adult colon. An in vitro study of the permeability of the colonic mucosa to oxalate and neutral sugars [ 521 suggests that the colon excludes molecules on the basis of size and charge. Bile acids and fatty acids increased absorption by increasing the number of transport sites but not the selectivity. Billich and Levitan 15.31 studied the effects of increasing os-

molality on net water movement in the human colon using mannitol and urea. They calculated an equivalent pore size of 2.3 A for the colon in comparison with the pore size of 8 A in the jejunum and 4 A in the ileum 1541. Lipid-soluble molecules are readily absorbed by passive diffusion [SO]. Organic acids and bases and drugs are, in general. most rapidly absorbed in their lipid-soluble undissociated form. This, along with the easy degradation of peptides in the gut lumen, has led to the development of chemically modified peptides for drug delivery in the colon. Insulin, which has been combined with palmitic acid to form palmatyl-insulin. has greater bioavailability [ 55 1. Observations of the absorption of organic acids and drugs from the colon led Schanker [SO] to suggest the existence of a more acid microclimate close to the mucosa. This has been contirmed in the guinea pig I.561 and rat [56,57] colon and the human rectum [57]. The pH measured at the mucosal surface of the human rectum is very stable and changes little despite large changes in luminal pH. The pH at the mucosal surface at 6.8 fell to only 6.26 when the luminal pH fell from 7.51 to 5.96. This pH microclimate is achieved by the secretion of H ’ 1% 1 produced by carbonic anhydrase on the mucosal membrane. The dissociation of a drug at the mucosal absorption site will thus depend on the relation of its pK,, to the pH of the microclimate and not to the pH of the bulk phase. The microclimate thickness is believed to be about 840 mm and is dependent on the integrity of the mucus layer [57]. The concentration of K- in the microclimate is also lower and independent of the luminal contents 1411, being closer to serosal values. This low K ’ concentration is probably maintained by a high pre-epithelial diffusion barrier and a high paracellular shunt, It is more stable in the proximal colon than in the distal colon 1421.

Carbohydrate which enters the colon, in any form, but mostly as dietary hbre, starch or mucopolysaccharides, is fermented by the colonic bacteria to short-chain fatty acids (SCFA); acetic, propionic and butryic acids. Amino acids are also metabolised to branched-chain SCFA isobutyric. isovaleric and valeric acids. It is now well established that these SCFA

are rapidly absorbed from the colon and are either: ( I ) used by the colonic epithelial cells for energy (this is mainly butyric acid 1591); (2) transported to the liver where propionic acid is metabolised and may influence hepatic cholesterol and glycogen synthesis [60,61]; (3) acetic acid passes into systemic blood and is used for energy or fat synthesis

1621. The mechanism of colonic SCFA absorption in man is thought to be by passive diffusion of the un-ionised form with luminal accumulation of bicarbonate 163,641. However, as SCFA pass through the pH microclimate of 6.8 at the mucosal surface (see above), most of the SCFA at the absorptive site should be in an ionised form 1571. This may explain the lack of effect of chain length and lipid solubility on the absorption of SCFA in the human rectum 1571. In the pony colon, both SCFA absorption mechanisms (with SCFA in both ionised and un-ionised forms) occur in the proximal colon but SCFA are absorbed predominantly in the ionised form in the distal colon [63]. Recent studies, using membrane vesicles of the apical and basolateral membranes of rat distal colonocytes, indicated that a bicarbonatedependent carrier mediated anion exchange was the major mechanism [65J for transport across the apical membrane, whereas butyrate has been shown to cross the basolateral membrane by both non-ionic and carrier-mediated SCFA-bicarbonate exchange mechanisms. Absorption of SCFA enhances the absorption of electrolytes and water 1661. Butyrate has been shown to largely reverse the effect of cholera toxin on water secretion in the rat in colonic loops in vivo 1671.

4. Barriers to absorption

As well as providing a stable pH environment, the mucus layer adjacent to the colonic mucosa also acts as a diffusion barrier [68]. Smith et al. [68] measured the movement of butyrate through the colonic mucus and compared it with movement through synthetic gels and the unstirred layer. They found no difference in the movement through mucus at different

C. Ed\twdc

I Advanced

Drug Deliwry

sites in the colon, but butyrate movement was only 50% of that through the unstirred layer and equivalent to its movement through an 8% polyacrylamide gel. Mucus production in the colon is a function of goblet cells, and as the proportion of goblet cells increases with age (though mainly due to a loss of other types of cell) this may be a factor that changes in the elderly [IS]. Mucins are degraded by the colonic bacterial flora 1691. Thus changes in the intestinal flora induced by diet or drugs may also affect the mucus layer. The mucus layer may also be affected by disease and is thinned by the action of prostaglandins [58]. 4.1.2. Unstirred water laver As material moves from the centre of the colonic lumen to the mucosa it passes through regions of decreasing mixing. At the mucosal surface, there is a layer of relatively unstirred water. All molecules must pass through this area by diffusion, and thus molecular size and other determinants of diffusibility, such as polarity, will affect the movement of a drug towards the mucosa. Some viscous soluble dietary fibres may increase the thickness of this layer by reducing intraluminal mixing. 1701 4.2. Bulk phase mixing and entrapment In the bulk phase, the physical properties of the luminal contents may also be important in determining rates of absorption. The fluid contents of the cecum and proximal colon are progressively dehydrated until they are only 70% water in the rectum. This reduction in water content means there is less mixing in the bulk phase and thus less access to the mucosal surface. Factors which change the amount of water retained in the colon such as soluble dietary fibre may increase the mobility and hence the absorption of molecules. However, many of the dietary fiber components with a higher water-holding capacity are fermented by the bacteria in the cecum and proximal colon, and hence lose their waterholding properties [7 11. Those fibres with high water holding capacity that are poorly fermented are often viscous (e.g. ispaghula) and this in itself will reduce mixing, though not to the extent of dehydrated feces. In the small intestine it is well established that viscous polysaccharides decrease the absorption of

Rrlkvs

28 (1997)

17.?-190

179

nutrients by inhibiting intraluminal mixing 1721. This has not been investigated in the colon.

4.3. Chemical

barriers

Some dietary fibres, such as pectin and chitosan 173,741, have cation-exchange properties which may bind charged molecules such as bile acids. This binding is increased at the low pH encountered in the colon [75], and may be a factor in the immobilisation of some drugs. In addition, drug molecules could be trapped within the solid matrix of the concentrated dietary residue or within the entangled chains of a soluble dietary fibre.

4.4. Microbiologicul

barriers

As already mentioned the colonic bacterial microflora is very numerous and possesses a vast and adaptable metabolic activity. The metabolic profile includes several enzymes which can deactivate, reactivate or degrade potential drugs or prodrugs [76]. This has been used in the development of targetted drug forms, such as sulphasalazine, other 5-aminosalicylic acid prodrug polymers 1771, and azoaromatic polymer-coated pellets containing insulin [781. The types of reactions carried out by the bacteria include: ( 1) hydrolysis of glucuronides, esters and amides; (2) aromatization of ethereal sulphates, sulphamates and glycosides; (3) reduction of carbon-carbon double bonds, nitro-acid A20 bonds, N-oxides, N-hydroxy compounds, carboxyl groups, alcohols phenols and arsenic acid: (4) degradation by decarboxylation, dealkylation, deamination and dehalogenation; and (5) synthesis by esterification, acetylation and formation of nitrosamines. The major bacterial enzymes studied are pglycosidase, P-glucuronidase, azoreductase, nitroreductase and 7a-hydroxysteroid dehydrogenase [79]. P-Glycosidase releases toxic metabolites of flavonoids from plants such as quercetin from rutin and kaempferol from robinin [SO]. P-Glucuronidase may be responsible for creating an enterohepatic circulation of certain drugs and toxic compounds such as dimethyl hydrazine (DMH) [S I] and 1-nitropyrene [82]. These are glucuronidated by the liver, eliminated in the bile and then

recycled to the liver by the bacterial P-glucuronidase in the colon. Azoreductase activity reduces water-soluble dyes such as methyl orange and methyl yellow to mutagenic and carcinogenic metabolites [ 831. Bacterial nitroreductase is responsible for formation of nitroso compounds and other harmful nitro reduction products 184). 7cu-Hydroxysteroid dehydroxylase is responsible for the dehydroxylation of bile acids to form secondary bile acids: deoxycholic acid and lithocholic acid [8S]. The activity of this enzyme has been linked to increased I-isk of colon cancer 18Sj. There are many other bacterial metabolic activities which may affect drug activity in the colon. Esterase hydrolyses digoxin to an inactive metabolite [861. Chloramphenicol is I-educed by nitroreductase, Glucuronide bonds in morphine glucuronide and oe+ tradiol are cleaved forming inactive molecules and sulfn pyrazone is reduced by sulfoxide reductase 1761. The enzymes which activate or inactivate drugs may be inducible or inhibited by pH or other luminal factors. Their activity may be affected by dietary fibre or other substrates for bacterial growth and metabolism or by antibiotics or other medicines. This area of bacterial transformation of drugs offers opportunities for the release of active forms of targetted prodrugs but the potentially harmful effects of some metabolites must be taken into account. Much more research is required.

The bacterial fermentation of carbohydrate itself also indirectly influences drug metabolism. Increased substrate availability for bacterial growth may increase the numbers of bacteria in the colon with the metabolic capability to transform and inactivate drugs. The production of SCFA may also have several indirect effects. As SCFA accumulate pH falls [87-891. This will affect the dissociation of a drug and also its binding to dietary residue. Ingestion of unabsorbed sugars. such as lactulose 1901. ot dietary fibre 187,891. may decrease colonic pH to as low as 5. The greatest decreases are seen in the proximal colon [ 89.901. SCFA also influence colonic motility 191,921 and transit time. and the water content of stool 1471. Furthermore, SCFA are trophic to the colonic epithelium. increasing the absorptive

surface area 1931 and probably absorptive capacity. SCFA also increase colonic blood flow [ 141. Furthermore SCFA enemas have been shown to improve symptoms of ulcerative colitis 1941

5. Colonic motility, residence

transit time and colonic

Motility patterns in the colon determine the rate of transit through the colon and hence the residence time of a drug. Contractions of the colonic wall also mix colonic contents and changes in mixing rate may influence absorption. It is therefore important to understand the patterns of colonic motility and the factors influencing them.

The smooth muscle of the human colon is composed of an inner continuous circular and an outer longitudinal layer. The longitudinal muscles comprise three strands (taeniae coli) which fuse together in the rectum. The mechanical properties of the proximal and distal colon muscle differ. Human colonic muscle taken at surgery from the right colon was more distensible than that of the left colon. and the maximum spontaneous active stress was exerted at greater degrees of stretch than those of the left colon 1951. The sigmoid colon produces the most powerful contractions in vitro [96] but the contractile frequency of the circular muscle of the right colon was greater than that of the left colon.

To fulfil the roles of fermentative chamber, propulsion and reservoir, each region of the colon has a different predominant motor pattern. Because of the inaccessibility of the human colon, and the necessary invasiveness of the techniques used to study motor patterns, it has been difficult to assess the role of different motility patterns and their relation to flow. Most colonic contractions consist of ring-like contractions of both longitudinal and circular muscle causing the relaxed areas to bulge outwards in haustra. These may move forwards or backwards or

remain stationary. The proximal colon has mainly retropulsive and mixing movements. The sigmoid colon has a degree of tonic and phasic motor activity and may hold colonic contents back in the descending colon to allow water absorption. The degree of tone or distensibility of the colon will determine the capacity of the colon to retain material after a meal. This tone varies diurnally increasing after meals and decreasing during sleep [97]. Atropine and morphine given intravenously increased the capacitance of the colon indicating one mode of action of antidiarrhoeal drugs [97].

5.2.1. Meimwernent of colonic motility Studies of colonic motility in vivo’usually rely on one of two methodologies: (1) measurement of changes in muscle electrical activity which may determine contractions; (2) measurement of contractile activity which can be observed as changes in colonic pressure caused by individual contractions, usually by monitoring resistance to the flow of slow infusions of fluid. Strain gauges may also be used to measure contractions more directly. All approaches provide useful information, but when used separately may not give a complete picture of colonic motor events. Electrical activity may not produce measurable contractions [9X], and manometric techniques can only detect contractions that occlude the lumen sufficiently to register as an increase in pressure (this is particularly important where the lumen is large and pressure increases are dampened). In vitro measurements using strips or segments of colon may suggest mechanisms and patterns of electrical and motor activity but the role of these must be assessed in vivo in an intact colon with enteric and ANS and CNS connections maintained. In vivo studies in man usually involve intubation and often bowel cleansing (sometimes with cathartics that may sensitise the colon [99]). It is difficult to assess whether the same motor patterns would be seen without the invasive tubes and with a colon full of chemically and mechanically stimulating contents.

5.2.2. Electrical basis of motility Contraction of the colonic muscles by the electrical activity of the

is determined muscle cells

(myogenic control). Periodic variations in the resting membrane potential determine the excitability of the muscle and the timing of contractions. When the membrane depolarises beyond a threshold potential the muscle generates an electrical response activity (ERA) which results in muscle contraction. Whether an ERA occurs or not is dependent on a neural or chemical signal occurring at the time of depolarisation 1981. The degree of coordination and organisation of the electrical activities and hence contractions is dependent on the coupling between adjacent muscle cells. This coupling may not be as efficient in the colon as in the small intestine. producing a disorganised or poorly phase-locked control activity and disorganised and short-duration contractions. This may also be related to a lack of gap junctions [961. Two types of control activity occur; electrical control activity (ECA) and contractile electric complex (CEC). Electrical control activity, or slow waves. is spontaneous, continuous [99,100] and has a frequency in the range of 2-13 cycles/min [ 1011. In the proximal colon these oscillations in membrane potential appear to migrate towards the mouth [ 1021. Those that originate in the mid-colon tend to spread towards the rectum. The slow wave can occur at a variety of frequencies depending on the level of stimulation [ 1011. Recorded slow-wave frequency in vivo may be the result of summation of different frequencies [loo]. ERA activity that superimposes on the ECA when stimulated at depolarisation, causing short duration contractions, is known as short spike bursts (SSB) [ 1031. They last less than 5 s and occur in series. These are thought to correspond to non-propagating haustral contractions and are most predominant in the proximal colon. The second type of control activity, the contractile electrical complex (CEC) is the oscillatory membrane potential which appears to be always associated with long-duration contractions [ 1041. These oscillations are intermittent and may require neural or chemical stimulation. They have a higher frequency than the ECA (slow waves): 24-36 cpm [99]. If neural or chemical signals occur when the CEC is below threshold, a different form of ERA occurs; long spike bursts (LSB) which last more than IO s and are associated with long duration-contractions that may propel contents along the colon [ 1041.

Very useful information has be gained from studies measuring contractile activity over long periods of time [ IOS]. In these studies manometric probes were placed in the colon at colonoscopy either in the rectum [ 1061, up to the transverse [ 1071 or through to the ascending colon [ I08 ]. The probes were left in place and motor patterns recorded for up to 24 h. All studies noted that the colon was very quiescent during sleep, whether this was at night or during the day. Indeed there was an increase in the motility index of the colon (a measure of the number and amplitude of contractions) when subjects were roused from resting and maintained at a more vigilant state by conversation 11091. Narducci and colleagues [107] recorded over 24 h and reported mainly low amplitude contractions which occurred singly or in bursts but which showed no recognisable pattern. The major stimulus for activity was awakening. High amplitude contractions which propagate over long distances at approximately 1 cm/s and are often associated with an urge to defecate have been recorded in several studies. These mass movements are thought to occur by relaxation of the gut in response to descending neural inhibition and the propagation of one ring-like contraction through colonic shortening initiated in the ascending or mid-transverse colon [106]. Movement of material towards the rectum can also occur with the long-duration contractions associated with the LSB. In contrast. the non-propagating contractions associated with SSB appear to act as baffles slowing transit through the intestine. In diarrhoea SSB activity is virtually absent 1I IO] but the motility is very active in constipation [I I1 1. This presents an apparent paradox in the colon. in that unless propagation is measured, an increase in colonic activity may in fact retlect a slowing of transit. Where there is an inhibition of motility and hence a decrease in motility index. this may be related to an increased flow and decreased transit time.

Various extrinsic stimulants of colonic motility have been reported. The most powerful is awakening from sleep or rest I 10%log]. The colonic motility

index is also increased after ingestion of a highcalorie meal ( 1000 kcal) [ 1121. This is often called the gastrocolic response. Very little stimulation is seen after a 350 kcal meal. ‘Mass movement’ contractions are not stimulated by a meal. There have been many studies of the gastrocolic response and a high-calorie meal is often used as the stimulus for the study of other factors influencing colonic motility. The mechanism for this response is not clear although it may involve hormonal [ 112I 1131and neural elements [ I 13,118]. Vagal efferent pathways appear to be involved [ 1171, but the role of pelvic nerves is unclear [ I I7,l 191. Colonic luminal pressure may modulate the gastrocolic response. When intracolonic pressure is low the colon does not respond to gastric distension but does if colonic pressure is high [ 1191. Physical exercise may also enhance the colonic response to meals ] 1 161. It has been suggested that, like other intestinal responses to food, there is a cephalic. a gastric and an intestinal phase I I 141. with colonic motility increasing at the sight and smell of food, the presence of food in the stomach and the presence of food in the intestine, both small and large. The cephalic phase was difticult to demonstrate [ 120- 1231 in some studies, but has been clearly reported in others [ 1241. This is probably because the effect is short lived in humans and we quickly adapt to the presence of food. The change in motor activity in response to food is made up of two components. The first is a rise in motility within 30 min of the meal, this must be related to food in the stomach or duodenum I I 121. Many studies have reported an immediate increase in colonic motility when food enters the stomach I I I2.120- 123, I2S- 1271 but there is an independent action of food in the small intestine. Colonic motor activity is stimulated by fat infusion directly into the duodenum, however, but not intravenous fat [12X], and colonic stimulation is also seen when magnesium sulphate, amino acids and sodium oleate are introduced in the duodenum [ 129,130]. There is a second increase in colonic motility about 70-90 min after the meal ]I 121. In the dog there appear to be three phases with an increase in motility at 5 min before and 2 and 8 h after the meal 1I3 I ]. This late response may be related to the entry of the meal into the colon. The stimulus in each region of the gut may be mechanical or chemical but in light of the inconsistent effect of gastric distension

[ 132,133] is more likely to be via chemoreceptors [114]. Most studies have concentrated on the distal colon, those studies which have measured motility in the more proximal colon have reported a different response to meals. In the dog the early postprandial phase was seen only in the distal colon and not the proximal, but the later phases were seen throughout the colon [ 13 11. A gastrocolic response has been observed in the mid and transverse colon of the human [107,133], and a small response seen in the proximal colon [ 1341, but this may relate to solid meals and not liquid meals 11351. Individual food components may specifically influence colonic motility. An increase in distal colonic motility was recorded in preselected ‘responders’ after ingestion of coffee (both normal and decaffeinated) but not after ingestion of hot water [ 1361. The other major general stimulant of colonic motility is stress. The interest of the effects of stress on the colon in man have centred around studies of irritable bowel syndrome (IBS) [ 1371. The effect of stress is very difficult to study and many different types of stress have been applied experimentally to man. None of these may relate to the stressful situations in real life which result from emotional or mental pressures [ 1371. Many studies involve physical stress such as immersing a hand in water at 4°C or instilling water at 4°C into the external auditory meatus of one ear. Mental stress tests involve tasks performed during distracting aural or visual stimuli such as two different audio tapes played simultaneously in either ear (dichotomous listening test). Several groups have shown an increase in colonic motility in response to physical stress [101,138,139]. Narducci et al [ 1381 found an increase in colonic motility in subjects given mental stress in the form of ‘ball sorting’ and Stroop test tasks (subjects had to read in fast sequence 50 cards on which the name of a colour was written in another colour). Erkenbrecht et al. [ 1391 however found no effect of mental stress on unstimulated colonic motility and a decrease in motility patterns after a meal when mental stress was applied as a dichotomous listening test. The classic studies of Almy et al. 11401 monitored colonic motor activity and appearance during interviews with patients with IBS about life events that the patients founds very emotionally stressful. They recorded increased colonic motility during the time talking about the stressful life event compared to

discussion

of neutral topics. Stress increased

motili-

ty. The intraluminal factors which influence colonic motility are particularly poorly understood. Distension by the luminal contents or gas produced by bacterial fermentation may induce propulsive activity [ 141,142]. Bile acids and hydroxy fatty acids have also been shown to stimulate propulsion [ 143-1451. The fermentative function of the proximal colon has encouraged speculation that the short-chain fatty acids produced by the bacteria may influence motility perhaps to prevent movement of material from the fermentation chamber allowing bacteria to maintain adequate populations. However, SCFA have been shown both to stimulate [91] and inhibit [92] colonic motility in the rat in vitro and had no effect on proximal colonic capacitance in the human [ 1461. Particulate matter such as dietary fibre residues in wheat bran or indeed plastic pellets [ 147-1501, also stimulate motility and produce more frequent and more liquid stool perhaps by stimulation of mechanoreceptors. The relationship of other physical properties of luminal contents, such as viscosity and density, and colonic motility, have not been studied in any detail but need investigation. 5.5. Transit time and residence The residence of a drug in any particular segment of the colon will determine its absorption at that site. The time taken for food to pass through the colon accounts for most of the time the food is in the gut. In normal subjects this is about 78 h for expulsion of 50% ingested markers [ 11, but may range from 18 to 144 h. Mean transit time measured after ingestion of markers for several days was 54.2 h 115 11. Transit of material through each section of the colon may be measured by ingestion of markers and subsequent X-ray 11521, or gamma scintigraphy after oral ingestion [153], or perfusion into the cecum [154]. Segmental transit of radio-opaque markers was 35 h for the whole colon and 11.3, 11.4 and 12.4 h for the right, left and rectosigmoid colon [ 1521. Whole colonic transit in another study using magnetised spheres was 43.5 h, with most of the time spent in the right colon [ 1551. Men had slightly shorter transit times than women and this was most apparent in the more proximal colon. [ 1521. X-ray studies have the advantage that the colon is full of solid material and

the subjects are on a normal diet. Subjects having transit measured by scintigraphic techniques where the radio-label is ingested in a meal also have a full colon but require higher doses of radiation if a short half-life isotope is used and complex analysis to compensate for overlap of small and large intestines 115.11. Studies where the radiolabel is infused directly into the colon allow more detailed measurements of colonic flow and transit, but are usually performed with a prepared or washed out colon so that the transit time of the contents is mainly that of the liquid infusate and may not relate to more solid material. Krevsky et al. [ 1.54) injected a bolus of 8 ml into the colon and monitored transit for 48 h. Most of the label had been defecated by this time. They reported a rapid emptying of the proximal colon of 88 min. and suggested that the transverse colon was a ma.jor storage site. Gamma scintigraphy has also been performed simultaneous with intraluminal pressure studies so that flow cm be related to motility. Using this technique it was shown that a high-calorie meal increased non-propagating contractions mainly in the descending colon and the radiotracer moved from the splenic flexure to the transverse and sigmoid colon [ 1561. When radiolabelled liquid and solid were introduced into unprepared colon, there was no significant difference in their transit through the different colonic regions [ 1571. Larger volumes of fluid, however, are likely to be handled differently. Colonic capacitance was measured [ 1461 by infusing radiotracer and measuring the volume of different areas of the colon. This showed that the right colon acted as a reservoir but the capacitance was reduced by oleic acid [ 145).

6. Factors affecting

transit time

Diet is a major influence on transit time. A lowresidue diet is associated with slow transit and small fecal output [ 1581. A high mixed tibre diet or a diet supplemented with poorly fermented dietary fibres. such as wheat bran or ispaghula, decreases the transit time and increases stool output [ 158-1601. This may be associated with an increase in LSB and a decrease in SSB [ 1471. The mechanism by which dietary fibre speeds transit through the colon is not well understood. There are probably several mechanisms and

each fibre has its own idiosyncratic action. Fibres with a large water-holding capacity that is retained after fermentation by the rich colonic flora may just increase the bulk of colonic contents 1711 and act by distension. Gas produced by fermentation may also act this way. The physical presence of dietary residue may stimulate mechanoreceptors as described above [ 147- ISO]. The best stool bulkers are the least fermented. Fermentation studies of different dietary tibres in vitro, compared with transit measurement in humans who had digested the same fibres, and who provided the inoculum for the in vitro studies, however. showed that transit time can be accelerated without an increase in stool output and fermentation was necessary for acceleration of transit time [ 161 I. The mechanism for this is not known. The factors determining segmental transit through the different regions of the colon are particularly poorly understood and more work is needed here. Transit time is slower in women than men and is related to the circulating steroid hormones in the rat, but the menstrual cycle does not seem to have an effect in women 1162%1651. Drugs and disease may affect transit, and this is particularly important in colonic disease where colonic administration of drugs may be necessary.

The rate of delivery of orally ingested drugs to the colon depends on the rate of gastric emptying and small bowel transit time. The transit of different dosage forms through the small intestine was monitored after ingestion with and without food [ 1661. Solutions and pellets emptied from the stomach with the food, but single units were retained in the stomach for some time. However, intestinal transit times were independent of dosage or food. There are many factors determining the movement of drugs through the small intestine [ 1671. These wil! not be discussed here. When the dosage forms reach the colon, the transit depends on size. Small particles pass through the colon more slowly than large units [ 167-1691, but the density and size of larger single units had no real effect on colonic transit. About 50% of large units reached the splenic flexure within 7 h of entering the colon independent of density [ 1691. Larger units had a tendency to travel more

quickly but this was not biologically significant. Similar results were gained in a study of IBS patients [ 1701. The range of transit times between individuals for non-disintregating tables through the large intestine is wide even when diet is similar and stasis may occur at several sites although mainly in the proximal colon [I711 Drugs administered to the colon by enema may have a limited spread reaching mainly the distal and mid transverse colon [ 1721. Spreading of enema solutions is directly related to the level of colonic motility although no significant effect of eating a meal has been identified [ 1731.

the absorption characteristics of different regions of the colon need to be determined in more detail. However, although there are great limits to our knowledge and understanding of the colorectal barriers to drug absorption, it is clear that the use of the colon as a preferred site for drug absoprtion is set to increase.

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