Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2485667 | Journal of Pharmaceutical Sciences | 2008 | 26 Pages |
Abstract
Intestinal firstâpass metabolism has a great impact on the bioavailability of CYP3A substrates in humans, and the in vivo impact has quantitatively been evaluated using CYP3A inhibitors or inducers. In vitro and in vivo preclinical investigations for intestinal metabolism are essential in clarifying pharmacokinetic behavior in animal species and predicting the effect of intestinal metabolism in the human. In this review, we will discuss species differences in intestinal CYP3A enzymes, and CYP3Aâmdediated intestinal elimination. Identical CYP3A4 enzyme is expressed in human intestine and liver, but different CYP3A enzymes in both tissues of the mouse and rat are found, that is, respective intestinal enzyme is considered as cyp3a13 and CYP3A62. There is little information on CYP3A enzymes in the monkey and dog intestine, unlike the liver. In vitro metabolic activities of midazolam and nisoldipine are higher in the human and monkey than in the rat. In vivo assessment of cyclosporine, midazolam, nifedipine, tacrolimus, and verapamil has been reported in various species (monkey, rat, mouse, and/or dog) including the human. For midazolam, the monkey shows significant in vivo intestinal metabolism, as evidenced in the human. The monkey might be an appropriate animal model for evaluating small intestinal firstâpass metabolism of CYP3A substrates.
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Authors
Hiroshi Komura, Masahiro Iwaki,