How important is intestinal cytochrome P450 3A metabolism?

Abstract:

:Cytochrome P450 3A (CYP3A) enzymes metabolize a wide variety of xenobiotics including many drugs. Because CYP3A is localized in both the liver and intestine, it can make a major contribution to the presystemic elimination of substrate drugs after oral administration ('first-pass metabolism'). However, assessments of the relative importance of intestinal versus hepatic CYP3A-mediated first-pass metabolism have been difficult to make and are subject to extensive discussion. To assess systematically the relative contributions of the intestine and liver to first-pass metabolism in vivo, Cyp3a knockout mice expressing human CYP3A4 in the liver or intestine have recently been generated. Analysis of these mice, together with previous observations in humans, substantiates that intestinal CYP3A4 can operate independently of the liver as a highly efficient metabolic barrier during the uptake of various drugs from the intestine. We expect that the insights obtained with these mouse models will contribute to the development of better oral drugs and treatment regimens.

journal_name

Trends Pharmacol Sci

authors

van Herwaarden AE,van Waterschoot RA,Schinkel AH

doi

10.1016/j.tips.2009.02.003

subject

Has Abstract

pub_date

2009-05-01 00:00:00

pages

223-7

issue

5

eissn

0165-6147

issn

1873-3735

pii

S0165-6147(09)00038-8

journal_volume

30

pub_type

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