Gut instincts: CYP3A4 and intestinal drug metabolism
Kenneth E. Thummel
Kenneth E. Thummel
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Commentary

Gut instincts: CYP3A4 and intestinal drug metabolism

Abstract

First-pass metabolism is a common cause of incomplete and variable absolute bioavailability for an orally dosed drug. The drug-metabolizing enzyme CYP3A4 is often implicated in this process, resulting, in some cases, in systemic exposures of less than 15% of the administered dose. By creating an elegant CYP3A4-transgenic mouse model, van Herwaarden et al. show in this issue of the JCI that first-pass metabolism of the anticancer agent docetaxel by the gut wall, and not the liver, is likely to be the major cause of its low oral bioavailability in humans (see the related article beginning on page 3583). This study helps explain interpatient differences in efficacy and safety following oral therapy with approved CYP3A4 substrates and provides a powerful new tool for preclinical predictions of first-pass metabolism for new drugs in development.

Authors

Kenneth E. Thummel

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Figure 1

Pharmacokinetic model depicting the effect of intestinal and hepatic first-pass metabolism on steady-state systemic blood concentrations of an orally administered drug ([P]art.ss).

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Pharmacokinetic model depicting the effect of intestinal and hepatic fir...
Sequential first-pass metabolism of the drug (P) to a metabolite (M) can occur in the enterocytes of the intestinal mucosa and in the hepatic parenchymal cells. This contributes, along with the fraction of the dose in the gut lumen that is absorbed into the enterocytes, to the absolute bioavailability of the oral dose. A reduction in oral bioavailability by first-pass metabolism has a proportional effect on the concentration of drug reaching the arterial blood circulation and, hence, the site of drug action. In this issue of the JCI, van Herwaarden et al. (1) show that selective intestinal expression of the human CYP3A4 gene in Cyp3a-knockout mice conferred high first-pass elimination of the anticancer agent docetaxel, in contrast to a more modest effect from selective hepatic CYP3A4 expression. art, arterial.