Abstract

The calcium channel blocker nifedipine is metabolized by cytochrome P450 3A4, which is present in liver and mucosa of the small bowel. Cytochrome P450 3A4 is inducible by the tuberculostatic rifampin in liver and the small bowel. The contribution of gut wall metabolism to total clearance of nifedipine before and during induction has not been determined in detail. We therefore investigated the nifedipine-rifampin interaction, with special emphasis on the contribution of gut wall metabolism to total metabolism of nifedipine before and during administration of rifampin. Pharmacokinetics of nifedipine were studied in six healthy volunteers on separate days by administration of 20 micrograms/kg body weight nifedipine iv and 20 mg nifedipine orally before and after 7 days of rifampin treatment (600 mg/day). Enzyme induction did not significantly alter pharmacokinetics of nifedipine after iv administration. In contrast, oral clearance of nifedipine increased from 1.5 +/- 0.2 liters/min to 20.9 +/- 8.3 liters/min (p < 0.01) and bioavailability decreased from 41.2 +/- 5.4% to 5.3 +/- 2.7% (p < 0.001). Although hepatic extraction of nifedipine was not significantly altered during induction (47.4 +/- 6.6% versus 67.4 +/- 20.2%; ns), the calculated extraction of nifedipine in gut wall mucosa increased from 21.8 +/- 13.3% to 75.8 +/- 28.2% (p < 0.05). We conclude that there is a relevant interaction between nifedipine and rifampin. The reduction of nifedipine bioavailability during enzyme induction is most likely due to rifampin-induced gut wall metabolism.