Determination of in vivo absorption, metabolism, and transport of drugs bythe human intestinal wall and liver with a novel perfusion technique

Background and Aims: The contribution of the gastrointestinal tract in comp arison with the liver for the low and variable bioavailability of orally ad ministered drugs is still poorly understood. Here we report on a new intest inal perfusion technique for the direct assessment of absorption, metabolis m, and transport of drugs by the intestinal wall. Methods: In 6 healthy volunteers a multilumen perfusion catheter was used t o generate a 20-cm isolated jejunal segment that was perfused with 80 mg ve rapamil. Simultaneously, 5 mg [H-2(7)]verapamil was given intravenously. Bl ood, perfusate, and bile samples were analyzed for parent verapamil and its major metabolites. Results: The mean fraction of the verapamil dose absorbed from the 20-cm se gment was 0.76 but substantial interindividual variability (0.51-0.96) was shown. Bioavailability was low (19.3%). The intestinal wall contributed to the same extent as the liver to extensive first-pass metabolism (mean extra ction ratio, 0.49 versus 0.48). Substantial transport of verapamil metaboli tes from the systemic circulation via the enterocytes into the intestinal l umen was observed. Compared with biliary excretion, intestinal secretion in to a 20-cm jejunal segment contributed to drug elimination to a similar ext ent. Conclusion: First-pass metabolism by the intestinal wall is extensive and c ontributes to the same extent as the liver to low bioavailability of some d rugs such as verapamil. Moreover, intestinal secretion is as important as b iliary excretion for the elimination of metabolites.