吡格列酮对维拉帕米及其主要代谢产物去甲维拉帕米在大鼠体内药代动力学的影响。

Effect of pioglitazone on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats.

作者信息

Choi Jun Shik, Burm Jin Pil

机构信息

College of Pharmacy, Chosun University, Gwangju, 501-759, Korea.

出版信息

Arch Pharm Res. 2008 Sep;31(9):1200-4. doi: 10.1007/s12272-001-1289-z. Epub 2008 Sep 20.

DOI:10.1007/s12272-001-1289-z

PMID:18806964

Abstract

Pioglitazone, a thiazolidinedione antidiabetic drug, inhibits cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes in vitro. This study investigated the effect of pioglitazone on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats, after oral administration of verapamil (9 mg/kg) in the presence or absence of pioglitazone (0.3 or 1.0 mg/kg). Pioglitazone altered verapamil pharmacokinetics compared with verapamil alone. The presence of 1.0 mg/kg of pioglitazone significantly (p < 0.05) increased the area under the plasma concentration-time curve (AUC) and the peak concentration (C(max)) of verapamil by 49.0% and 46.8%, respectively, and significantly (p < 0.05) decreased the total plasma clearance (CL/F) of verapamil by 32.8%. The metabolite-parent AUC ratio in the presence of pioglitazone (1.0 mg/kg) significantly (p < 0.05) decreased by 21.9% compared to the control group. Thus, coadministration of pioglitazone inhibited the CYP3A4-mediated metabolism of verapamil.

摘要

吡格列酮是一种噻唑烷二酮类抗糖尿病药物，在体外可抑制细胞色素P450（CYP）2C8和CYP3A4酶。本研究在大鼠口服维拉帕米（9 mg/kg）的同时给予或不给予吡格列酮（0.3或1.0 mg/kg），考察吡格列酮对维拉帕米及其主要代谢产物去甲维拉帕米药代动力学的影响。与单独使用维拉帕米相比，吡格列酮改变了维拉帕米的药代动力学。给予1.0 mg/kg吡格列酮时，维拉帕米的血浆浓度-时间曲线下面积（AUC）和峰浓度（C(max)）分别显著（p < 0.05）增加49.0%和46.8%，维拉帕米的总血浆清除率（CL/F）显著（p < 0.05）降低32.8%。与对照组相比，给予吡格列酮（1.0 mg/kg）时代谢产物与母体的AUC比值显著（p < 0.05）降低21.9%。因此，联合使用吡格列酮可抑制CYP3A4介导的维拉帕米代谢。