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).

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.