Piao Yong-Ji, Li Xiuguo, Choi Jun-Shik
College of Pharmacy, Chosun University, Kwangju, Republic of Korea.
Eur J Drug Metab Pharmacokinet. 2008 Jul-Sep;33(3):159-64. doi: 10.1007/BF03191113.
Etoposide is mainly metabolized by cytochrome P450 (CYP) 3A and is a substrate for P-glycoprotein (P-gp). This study examined the effects of verapamil, a CYP3A and P-gp inhibitor, on the pharmacokinetics of etoposide in rats. A single dose of etoposide was administered via oral (p.o.; 10 mg/kg) or intravenous (i.v.; 3.3 mg/kg) routes to rats alone (control animals) or together in combination with verapamil (2 or 6 mg/kg; experimental animals). The presence of verapamil significantly increased the area under the plasma concentration-time curve (AUC); (P < 0.05; 39.2-47.6%) and significantly reduced (P < 0.01; 27.8-31.2%) the total body clearance (CLt) of p.o. administered etoposide. The absolute bioavailability (F) of etoposide increased by 1.38- to 1.47-fold. The presence of verapamil significantly increased (P < 0.01; 38.3-38.9%) the AUC and significantly reduced (P < 0.01; approximately 27%) the total body clearance (CLt) of i.v. administered etoposide. This increased bioavailability suggests that verapamil inhibits metabolic activity and elimination etoposide. The increased bioavailability of etoposide in the presence of verapamil should be taken into consideration for dosage regimens due to a potential drug interaction (DI).
依托泊苷主要通过细胞色素P450（CYP）3A代谢，是P-糖蛋白（P-gp）的底物。本研究考察了CYP3A和P-gp抑制剂维拉帕米对大鼠体内依托泊苷药代动力学的影响。单独给大鼠（对照动物）经口服（10 mg/kg）或静脉注射（3.3 mg/kg）途径给予单剂量依托泊苷，或与维拉帕米（2或6 mg/kg；实验动物）联合给药。维拉帕米的存在显著增加了血浆浓度-时间曲线下面积（AUC）（P<0.05；39.2-47.6%），并显著降低了口服给药依托泊苷的总体清除率（CLt）（P<0.01；27.8-31.2%）。依托泊苷的绝对生物利用度（F）提高了1.38至1.47倍。维拉帕米的存在显著增加了静脉注射给药依托泊苷的AUC（P<0.01；38.3-38.9%），并显著降低了其总体清除率（CLt）（P<0.01；约27%）。这种生物利用度的提高表明维拉帕米抑制了依托泊苷的代谢活性和消除。由于潜在的药物相互作用（DI），在制定给药方案时应考虑维拉帕米存在时依托泊苷生物利用度的提高。
