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

Background and Aims The contribution of the gastrointestinal tract in comparison with the liver for the low and variable bioavailability of orally administered drugs is still poorly understood. Here we report on a new intestinal perfusion technique for the direct assessment of absorption, metabolism...

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Published in:Clinical pharmacology and therapeutics 2001-09, Vol.70 (3), p.217-227
Main Authors: Richter, Oliver, Greiner, Bernd, Fromm, Martin F., Fraser, Robert, Omari, Taher, Barclay, Murray L., Dent, John, Somogyi, Andrew A., Eichelbaum, Michel
Format: Article
Language:English
Subjects:
Adult
Algorithms
Area Under Curve
Bile - metabolism
Biological and medical sciences
Biological Availability
Biological Transport
Calcium Channel Blockers - pharmacokinetics
General pharmacology
Humans
Intestinal Absorption - physiology
Intestines - metabolism
Liver - metabolism
Male
Medical sciences
Middle Aged
Perfusion
Pharmaceutical Preparations - metabolism
Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions
Pharmacology. Drug treatments
Verapamil - pharmacokinetics
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Summary:Background and Aims The contribution of the gastrointestinal tract in comparison with the liver for the low and variable bioavailability of orally administered drugs is still poorly understood. Here we report on a new intestinal perfusion technique for the direct assessment of absorption, metabolism, and transport of drugs by the intestinal wall. Methods In 6 healthy volunteers a multilumen perfusion catheter was used to generate a 20‐cm isolated jejunal segment that was perfused with 80 mg verapamil. Simultaneously, 5 mg [2H7]verapamil was given intravenously. Blood, 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 segment 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 extraction ratio, 0.49 versus 0.48). Substantial transport of verapamil metabolites from the systemic circulation via the enterocytes into the intestinal lumen was observed. Compared with biliary excretion, intestinal secretion into a 20‐cm jejunal segment contributed to drug elimination to a similar extent. Conclusion First‐pass metabolism by the intestinal wall is extensive and contributes to the same extent as the liver to low bioavailability of some drugs such as verapamil. Moreover, intestinal secretion is as important as biliary excretion for the elimination of metabolites. Clinical Pharmacology & Therapeutics (2001) 70, 217–227; doi: 10.1067/mcp.2001.117937
ISSN:0009-9236
1532-6535
DOI:10.1067/mcp.2001.117937