![]() Effect of intestinal and hepatic metabolism on the bioavailability of tacrolimus in rats. Evidence for induction of gut wall metabolism. Holtbecker N, Fromm M, Kroemer HK, et al. First-pass metabolism of cyclosporin by the gut. Intestinal MDR transport proteins and P-450 enzymes as barriers to oral delivery. J Pharmacol Ther 1998 285: 1104–12īenet LZ, Izumi T, Zhang Y, et al. Metabolism and transport of the macrolide sirolimus in the small intestine. First-pass effect: significance of the intestine for absorption and metabolism. J Pharmacol Exp Ther 1997 283: 1552–62ĭoherty MM, Pang KS. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP 3A4-medated metabolism. Intestinal drug absorption and metabolism II: kinetic aspects of intestinal glucuronide conjugation. Route-dependent metabolism of morphine in the vascularly perfused rat small intestine preparation. ![]() Clin Pharmacol Ther 1997 62: 41–9ĭoherty MM, Pang KS. Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin Pharmacol Ther 1996 60: 14–24įloren LC, Berkersky I, Benet LZ, et al. First-pass metabolism of midazolam by human intestine. Differentiation of absorption and first-pass gut metabolism in humans: studies with cyclosporin. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Hebert MF, Roberts JP, Prueksaritanont T, et al. Identification of glucocorticoid-inducible cytochrome P-450 in the intestinal mucosa of rats and man. Watkins PB, Wrighton SA, Schuetz E, et al. Localization and characterization of drug-metabolizing enzymes along the villus-crypt surface of the rat small intestine. Biochem Pharmacol 1988 37: 169–76ĭubey RK, Singh J. Localization and characterization of drag-metabolizing enzymes along the villus-crypt surface of the rat small intestine. Pharmacol Ther 1990 46: 67–93ĭubey RK, Singh J. Metabolism of drags and other xenobiotics in the gut lumen and wall. In order to achieve this, the first-pass contributions of the intestine and liver must be successfully decoupled. Much work is yet to be done in characterising the clinical impact of other enzyme systems on drug therapy. An overwhelming proportion of clinically relevant drug interactions where the intestine has been implicated as a major contributor to first-pass metabolism involve drugs that undergo cytochrome P450 (CYP) 3A4-mediated biotransformation and are substrates for the efflux transporter P-glycoprotein. This variability can stem from genetic (metabolising enzyme polymorphisms) and/or non-genetic (including concomitant drug and food intake, route of administration) sources. The clinical relevance of intestinal metabolism, however, depends on the relative importance of the metabolic pathway involved, the therapeutic index of the drug and the inherent inter- and intra-individual variability. ![]() ![]() An understanding of the interplay between the processes controlling absorption, metabolism and P-glycoprotein-mediated efflux from the intestinal mucosa into the intestinal lumen facilitates determination of the extent of the intestinal contribution to first-pass metabolism. This review discusses the intestinal properties and processes that contribute to drug metabolism. ![]() This has been supported by clinical studies of orally administered drugs (well-known examples include cyclosporin, midazolam, nifedipine and tacrolimus) where intestinal drug metabolism has significantly reduced oral bioavailability. Increasingly, as a result of in vitro and in vivo (animal and human) data, the intestinal mucosa is being implicated as a major metabolic organ for some drugs. The intestinal mucosa is capable of metabolising drugs via phase I and II reactions. ![]()
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