Controlled entry of orally administereddrugs: physiological considerations

Abstract

Physiological considerations bearing on the controlle entry into the systemic circulation of orally administered drugs in healthy man are reviewed. The most desirable site for drug absorption is the sterile portion of the small intestine, so that the time “window” available for absorption is not greater than the minimum small intestinal residence time in this segment. This appears to vary widely between individuals. Methodology for sampling intestinal content and for defining the fraction absorbed and the physical state of an administered drug are summarized. Small intestinal transit and gastric emptying rates are now estimated in man by imaging techniques using Tc99m labeled sulfur colloids. Small intestinal transit may also be estimated non-invasively by measuring breath H2 after administration of a meal containing a non-absorbable disaccharide such as lactulose, but the validity of such a method is uncertain because of the acceleration of intestinal transit by lactulose. The major determinants of small intestinal transit in the fasting state is the interdigestive motor complex. During digestion, complex neurohumoral factors influence transit. Literature values for small intestinal transit are tabulated. The biochemical and physical features of the micro-environment of the stomach and small intestine during the fasting state and digestive state are reviewed. First-pass considerations are outlined, and the need for developing physiological pharmacokinetic models stressed. Available data suggest that 2–3 hours is the maximum time available for the absorption of any drug in the sterile region of the small intestine. Therefore, future therapeutic efforts aimed at slowing absorption should probably be aimed at slowing gastric emptying, unless passage of drug into the colon is judged acceptable. For rational design of controlled entry drugs, greater cooperation between the gastroenterologist and the pharmaceutical scientist appears needed.