Physiological Pharmaceutics

150 Physiological Pharmaceuticssodium-potassium pump in the basolateral membrane of epithelial cells creates a highintracellular potassium concentration (80 mM), of which only a small proportion is lost tothe colonic lumen, since the apical epithelial membrane is essentially impermeable topotassium.pHStudies using a pH sensitive radiotelemetry capsule in normal, ambulatory volunteers haveshown that the mean pH in the colonic lumen is 6.4 ± 0.6 in the ascending colon, 6.6±0.8in the transverse colon and 7.0±0.7 in the descending colon 10 .Many factors such as disease, diet, pharmaceutical formulations or therapeutic agentsmay alter the pH or the difference in pH between the ascending and descending colon. Forexample, administration of the laxative disaccharide lactulose causes the production of largeamounts of lactic acid by the caecal bacteria, acidifying the proximal colon to 5.5–5.0. Lesspronounced decreases are produced by guar gum and isphagula. Evidence exists suggestingthat there are substantial changes in gastrointestinal pH in patients with malabsorption dueto cystic fibrosis and in ulcerative colitis the pH may drop below 5 11 . Current dosage formsdesigned for release in the proximal bowel employ enteric coatings, and are thereforedependent on luminal pH. Alteration of the pH profile of the gastrointestinal tract in variousdisease states may be an important factor influencing the bioavailability of drugs deliveredin this form.BacteriaThe gastrointestinal tract is sterile at birth, but colonization typically begins within a fewhours of birth, starting in the small intestine and progressing caudally over a period ofseveral days. In most circumstances, a “mature” microbial flora is established by 3 to 4weeks of age. The colonic microflora contain up to 400 different species of both aerobic andanaerobic bacteria and make up approximately 30% of faecal dry weight. The mostprevalent anaerobes are Bacteroides sp. and Bifidobacterium whilst the most numerousaerobes are Escherichia coli, enterococci and Lactobacillus. The major site of bacterialactivity is the caecum where the anaerobic bacteria ferment substrates in a liquid mixture.The principal sources of nutrition for the bacteria are complex carbohydrates includingstarches, non-starch polysaccharides including dietary fibre (celluloses, gums and pectins)and smaller saccharides such as lactose, sorbitol and xylitol. It is thought that 2–20% ofdietary starch escapes absorption in the small bowel. Synthesis of vitamin K by colonicbacteria provides a valuable supplement to dietary sources and makes clinical vitamin Kdeficiency rare.Cellulose is a common constituent in the diet of many animals, including man, but nomammalian cell is known to produce a cellulase. Several species of bacteria in the largebowel synthesize cellulases and digest cellulose, and the major end products of digestion ofthis and other carbohydrates are volatile fatty acids, lactic acid, methane, hydrogen andcarbon dioxide. Fermentation is thus the major source of intestinal gas. Volatile fatty acids(acetic, proprionic and butyric acids) generated from fermentation can be absorbed bypassive diffusion in the colon and metabolised in the epithelial cells and liver. Short chainfatty acids remaining in the colon are neutralised by bicarbonate ions which are secreted intothe lumen.In man, the metabolic activity of the caecal bacteria can be demonstrated byingestion of lactulose or baked beans which are fermented by the caecal bacteria, causinga rise in breath hydrogen. This is used as a method of estimating the time of mouth tocaecal transit.