Differential induction of prehepatic and hepatic metabolism of verapamil by rifampin

Abstract

Cytochrome P450 (CYP) enzymes, which metabolize numerous drugs, are expressed both in liver and in extrahepatic tissues. CYP3A4 for example is present and inducible by rifampin in epithelial cells of the gastrointestinal tract. It has been shown that such prehepatic metabolism contributes 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 oral and intravenous administration using a stable isotope technology. This approach allows us to exclude intraindividual day-to-day variability and is therefore suitable to quantitatively assess prehepatic extraction of high-clearance drugs. Moreover, because verapamil is administered as a race-mate with the S-enantiomer being preferentially metabolized, 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 deuterated 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-interval prolongation Rifampin increased the systemic clearance of the active S-verapamil 1.3-fold (P < .001). In contrast, rifampin increased the apparent oral clearance of S-verapamil 32-fold (P < .001) and decreased its bioavailability 25-fold (P < .001), with partial recovery after rifampin withdrawal (P < .01). With rifampin, the effect of oral verapamil on atrioventricular conduction was nearly abolished (P < .01), whereas no significant changes were observed after intravenous administration. Induction caused a considerable reduction of stereoselectivity after both intravenous and oral administration (P < .001). Rifampin altered the pharmacokinetics and the pharmacological effects of verapamil to a much greater extent after oral administration compared with intravenous administration. These data clearly indicate that prehepatic metabolism of verapamil (presumably in the gut wall) is preferentially induced compared with hepatic metabolism and that stereoselectivity of verapamil metabolism is affected by induction.

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

“…A similar study was reported in humans given intravenous and oral doses of verapamil, and the half-life of decrease in CYP3A activity after RIF withdrawal was estimated to be 1.5 to 2.1 days (Fromm et al, 1996). In another clinical study, urinary ratios of 6␤-hydroxycortisol to cortisol, an endogenous marker for CYP3A activity, returned to preinduction levels 11 days after RIF treatment was stopped (Tran et al, 1999), and the mean half-life of the return from maximum to basal levels was estimated to be 3 days (Yang et al, 2008).…”

“…Monkeys also show poor oral bioavailability for other CYP3A substrates such as verapamil (ϳ1%), nifedipine (ϳ1%), methotrexate (8%), and simvastatin (0.8%), which are therefore not well suited for in vivo enzyme induction study (Ogasawara et al, 2009b;Takahashi et al, 2009). In addition, CYP3A is known to be induced in the small intestine as well as in the liver, and clinical studies have shown that repeated oral administration of representative CYP3A inducers, such as RIF and St. John's wort, resulted in the up-regulation of CYP3A expression in the small intestine (Tannergren et al, 2004;Glaeser et al, 2005) and increased intestinal first-pass metabolism of verapamil, another CYP3A substrate (Fromm et al, 1996). In this study, we used alprazolam (APZ), a known CYP3A probe in humans as well (Schmider et al, 1999) as a marker substrate for pharmacokinetic studies in monkeys.…”

No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis

“…42 Biotransformation in gut wall contributes substantially to the overall first-pass metabolism of many CYP3A substrates. 43 It is noteworthy that CYP3A4 protein content is approximately three times higher in enterocyte homogenates than in paired liver homogenates. 44 Budesonide is a dual substrate of CYP3A and P-glycoprotein.…”

Inhibitory Effects of Silibinin on Cytochrome P‐450 Enzymes in Human Liver Microsomes

“…Furthermore, the presence of high concentrations of silibinin in the gut just after oral intake and/or as the result of an enterohepatic recirculation may affect gut wall metabolism. CYP3A4 is a major drug metabolising enzyme in the gut wall and makes an important contribution to first pass metabolism of many orally administered CYP3A4 substrates (Fromm et al 1996;Fuhr 1998). Inhibition of intestinal CYP3A4 is the reason for grapefruit juice interactions, which may cause a more than 100% increase in bioavailability of drugs undergoing pronounced first-pass metabolism by gut wall CYP3A4 (Fuhr 1998).…”