pared with intravenous administration. These data Cytochrome P450 (CYP) enzymes, which metabolize clearly indicate that prehepatic metabolism of veranumerous drugs, are expressed both in liver and in expamil (presumably in the gut wall) is preferentially intrahepatic tissues. CYP3A4 for example is present and duced compared with hepatic metabolism and that sterinducible by rifampin in epithelial cells of the gastroineoselectivity of verapamil metabolism is affected by testinal tract. It has been shown that such prehepatic induction. (HEPATOLOGY 1996;24:796-801.) metabolism contributes substantially to total clearance of CYP3A4 substrates (e.g., cyclosporine) before and even more pronounced during enzyme induction. We ex-Cytochrome P450 (CYP)-catalyzed drug metabolism and amined the effect of enzyme induction on prehepatic its induction have been assumed to occur predominantly in and hepatic metabolism of the model compound R/Sthe liver. However, there is increasing knowledge about exverapamil after simultaneous oral and intravenous adtrahepatic expression of cytochrome P450 enzymes, e.g., in ministration using a stable isotope technology. This apgastrointestinal mucosa. [1][2][3][4][5][6] Recently, CYP3A4, which metaboproach allows us to exclude intraindividual day-to-day lizes a broad variety of drugs (e.g., cyclosporine, quinidine, variability and is therefore suitable to quantitatively asnifedipine, diltiazem, verapamil, midazolam), has been sess prehepatic extraction of high-clearance drugs.
shown to be present and to be inducible by rifampin (rifampi-Moreover, because verapamil is administered as a racecin) in human small intestine. 2 Data from Kolars et al., 7 Hemate with the S-enantiomer being preferentially metabbert et al., 8 and Gomez et al. 9 clearly indicate that the immuolized, we investigated the influence of induction on nosuppressant cyclosporine, for example, is metabolized to a stereoselectivity of prehepatic and hepatic metabolism.
considerable extent in the gut wall mucosa. This prehepatic Eight male volunteers received 120 mg of racemic verametabolism can be induced by rifampin or inhibited by ketopamil bid for 24 days. Rifampin (600 mg daily) was given conazole, leading to relevant changes in bioavailability. 8,9 from day 5 to day 16. Systemic clearance and bioavail-
We addressed the question of the contribution of prehepatic ability of the verapamil enantiomers were determined and hepatic enzymes to total clearance of the frequently used by coadministering deuterated verapamil intravenously calcium channel blocker R/S-verapamil employing a stable on day 4, on day 16, and on day 24. Effects of verapamil isotope technology. 10 Prehepatic and hepatic metabolism are on atrioventricular conduction after oral and intravedetermined by simultaneous oral and intravenous (iv) adminnous (iv) administration were assessed by measuring the istration of the unlabelled and deuterium-labelled drug, remaximum PR-interval prolongation. Rifampin inspectively. This approach excludes day-to-day variability in creased the systemic clearance of the active S-verapamil drug disposition and enables exact quantification of prehe-1.3-fold (P Γ΅ .001). In contrast, rifampin increased the patic and hepatic extraction of high-clearance drugs during apparent oral clearance of S-verapamil 32-fold (P Γ΅ .001) chronic administration. and decreased its bioavailability 25-fold (P Γ΅ .001), with
Verapamil was chosen as a model drug for the following partial recovery after rifampin withdrawl (P Γ΅ .01). With reasons: First, the metabolism of verapamil has been studied rifampin, the effect of oral verapamil on atrioventricular in detail and the contribution of different cytochrome P450 conduction was nearly abolished (P Γ΅ .01), whereas no enzymes (CYP3A4, CYP1A2, CYP2C) to its metabolism has significant changes were observed after intravenous adbeen characterized. [11][12][13] Second, aspects of stereoselectivity ministration. Induction caused a considerable reduction can be investigated, because cardiovascular effects (PR-interof stereoselectivity after both intravenous and oral adval prolongation) of racemic verapamil are attributable ministration (P Γ΅ .001). Rifampin altered the pharmacomainly to the S-enantiomer. 14 Because of the racemic nature kinetics and the pharmacological effects of verapamil to of verapamil, inducibility of the metabolism of a high cleara much greater extent after oral administration comance drug (S-verapamil) and an intermediate clearance drug (R-verapamil) can be investigated in a single study. Finally, there is a correlation between the drug effect (PR-interval Abbreviations: CYP, cytochrome P450; iv, intravenous; AUC, area under the serum prolongation) and S-verapamil serum concentration, 15 which concentration time curve; CL, serum clearance; CLo, apparent oral clearance; F, bioavailabil-allows us to monitor the pharmacodynamic consequences of ity; FABS, fraction of orally administered verapamil, which is absorbed from the gut; EGI, induction. fraction of absorbed verapamil, which is metabolized in the gut wall mucosa; EL, fraction The antibiotic rifampin has a strong potential to interfere of verapamil in the portal vein, which is metabolized in liver; CLblood, blood clearance; QH, liver blood flow. with concomitant pharmacotherapy because of its enzyme From the Dr. Margarete Fischer-Bosch-Institut fu Β¨r Klinische Pharmakologie, Stuttgart, inducing properties. 16 It has seen a considerable renaissance Germany, and the Abteilung fu Β¨r Klinische Pharmakologie, Eberhard-Karls-Universita Β¨t Tu Β¨in the era of new or reemerging infectious diseases (e.g., tubingen, Germany.
berculosis) and therefore many of rifampin induced interac-