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.