DIFFERENTIAL INDUCTION OF PREHEPATIC AND HEPATIC-METABOLISM OF VERAPAMIL BY RIFAMPIN

Cytochrome P450 (CYP) enzymes, which metabolize numerous drugs, are ex pressed both in liver and in extrahepatic tissues. CYP3A4 for example is present and inducible by rifampin in epithelial cells of the gastro intestinal tract. It has been shown that such prehepatic metabolism co ntributes substantially to total clearance of CYP3A4 substrates (e.g., cyclosporine) before and even more pronounced during enzyme induction . We examined the effect of enzyme induction on prehepatic and hepatic metabolism of the model compound R/S-verapamil after simultaneous ora l and intravenous administration using a stable isotope technology. Th is approach allows us to exclude intraindividual day-to-day variabilit y and is therefore suitable to quantitatively assess prehepatic extrac tion of high-clearance drugs. Moreover, because verapamil is administe red as a racemate with the S-enantiomer being preferentially metaboliz ed, we investigated the influence of induction on stereoselectivity of prehepatic and hepatic metabolism. Eight male volunteers received 120 mg of racemic verapamil bid for 24 days. Rifampin (600 mg daily) was given from day 5 to day 16. Systemic clearance and bioavailability of the verapamil enantiomers were determined by coadministering deuterate d verapamil intravenously on day 4, on day 16, and on day 24. Effects of verapamil on atrioventricular conduction after oral and intravenous (iv) administration were assessed by measuring the maximum PR-interva l prolongation. Rifampin increased the systemic clearance of the activ e S-verapamil 1.3-fold (P < .001). In contrast, rifampin increased the apparent oral clearance of S-verapamil 32-fold (P < .001) and decreas ed its bioavailability 25-fold (P < .001), with partial recovery after rifampin withdrawl (P < .01). With rifampin, the effect of oral verap amil on atrioventricular conduction was nearly abolished (P < .01), wh ereas no significant changes were observed after intravenous administr ation. Induction caused a considerable reduction of stereoselectivity after both intravenous and oral administration (P < .001). Rifampin al tered the pharmacokinetics and the pharmacological effects of verapami l to a much greater extent after oral administration compared with int ravenous administration. These data clearly indicate that prehepatic m etabolism of verapamil (presumably in the gut wall) is preferentially induced compared with hepatic metabolism and that stereoselectivity of verapamil metabolism is affected by induction.