Fromm M F, Busse D, Kroemer H K, Eichelbaum M
Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.
Hepatology. 1996 Oct;24(4):796-801. doi: 10.1002/hep.510240407.
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.
细胞色素P450（CYP）酶可代谢多种药物，在肝脏和肝外组织中均有表达。例如，CYP3A4存在于胃肠道上皮细胞中，且可被利福平诱导。研究表明，这种肝前代谢对CYP3A4底物（如环孢素）的总清除率有很大贡献，在酶诱导前就有影响，诱导期间影响更显著。我们使用稳定同位素技术，在同时口服和静脉给药后，研究了酶诱导对模型化合物R/S-维拉帕米肝前和肝脏代谢的影响。这种方法使我们能够排除个体内每日的变异性，因此适合定量评估高清除率药物的肝前摄取。此外，由于维拉帕米是以消旋体形式给药，其中S-对映体优先被代谢，我们研究了诱导对肝前和肝脏代谢立体选择性的影响。8名男性志愿者每天两次服用120mg消旋维拉帕米，共24天。从第5天至第16天给予利福平（每日600mg）。在第4天、第16天和第24天静脉给予氘代维拉帕米，以测定维拉帕米对映体的全身清除率和生物利用度。通过测量最大PR间期延长来评估口服和静脉注射维拉帕米后对房室传导的影响。利福平使活性S-维拉帕米的全身清除率增加了1.3倍（P<.001）。相比之下，利福平使S-维拉帕米的表观口服清除率增加了32倍（P<.001），并使其生物利用度降低了25倍（P<.001），停药后部分恢复（P<.01）。使用利福平后，口服维拉帕米对房室传导的影响几乎消失（P<.01），而静脉给药后未观察到显著变化。诱导导致静脉和口服给药后立体选择性均显著降低（P<.001）。与静脉给药相比，口服给药后利福平对维拉帕米的药代动力学和药理作用影响更大。这些数据清楚地表明，与肝脏代谢相比，维拉帕米的肝前代谢（可能在肠壁）更易被诱导，且维拉帕米代谢的立体选择性受诱导影响。
