INTESTINAL DRUG-METABOLISM AND ANTITRANSPORT PROCESSES - A POTENTIAL PARADIGM SHIFT IN ORAL-DRUG DELIVERY

Poor oral bioavailability for many drugs is generally attributed to po or solubility in the gastrointestinal fluids, poor gut membrane permea bility and/or extensive hepatic first-pass elimination. Recently, howe ver, it has been recognized that cytochrome P-450 3A mediated drug met abolism in the intestine, and P-glycoprotein counter-transport process es may also contribute significantly to poor drug bioavailability. We have shown that cyclosporin, a highly lipid soluble, large molecular w eight compound does not appear to have absorption problems, with appro ximately 86% of the present commercial formulation being absorbed inta ct in healthy volunteers. Rather, the low bioavailability of cyclospor in results from extensive metabolic extraction in the gut which approa ches 60%. Recently, a strong overlap has been identified between subst rates for gut metabolism by cytochrome P-450 3A and gut counter-transp ort by P-glycoprotein, suggesting that these processes may work togeth er to limit the bioavailability of a large number of drug substances. Recognition of this potential for metabolism and counter-transport pro cess in the gut leads to a new perspective on improving drug bioavaila bility that differs from the traditional physico-chemical approach.