Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.
Clin Pharmacol Ther. 2013 Sep;94(3):383-93. doi: 10.1038/clpt.2013.92. Epub 2013 May 8.
Cytochrome P450 (CYP) 3A4 is considered the most important enzyme in imatinib biotransformation. In a randomized, crossover study, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3, to study the significance of CYP2C8 in imatinib pharmacokinetics. Unexpectedly, gemfibrozil reduced the peak plasma concentration (Cmax) of imatinib by 35% (P < 0.001). Gemfibrozil also reduced the Cmax and area under the plasma concentration-time curve (AUC0-∞) of N-desmethylimatinib by 56 and 48% (P < 0.001), respectively, whereas the AUC0-∞ of imatinib was unaffected. Furthermore, gemfibrozil reduced the Cmax/plasma concentration at 24 h (C24 h) ratios of imatinib and N-desmethylimatinib by 44 and 17% (P < 0.05), suggesting diminished daily fluctuation of imatinib plasma concentrations during concomitant use with gemfibrozil. Our findings indicate significant participation of CYP2C8 in the metabolism of imatinib in humans, and support involvement of an intestinal influx transporter in imatinib absorption.
细胞色素 P450（CYP）3A4 被认为是伊马替尼生物转化中最重要的酶。在一项随机、交叉研究中，10 名健康受试者每天两次给予吉非贝齐 600mg 或安慰剂，连续 6 天，并在第 3 天给予伊马替尼 200mg，以研究 CYP2C8 在伊马替尼药代动力学中的意义。出乎意料的是，吉非贝齐使伊马替尼的峰血浆浓度（Cmax）降低了 35%（P<0.001）。吉非贝齐还使 N-去甲基伊马替尼的 Cmax 和血浆浓度-时间曲线下面积（AUC0-∞）分别降低了 56%和 48%（P<0.001），而伊马替尼的 AUC0-∞不受影响。此外，吉非贝齐使伊马替尼和 N-去甲基伊马替尼的 Cmax/血浆浓度在 24 小时（C24 h）比值分别降低了 44%和 17%（P<0.05），提示与吉非贝齐同时使用时，伊马替尼的血浆浓度日波动减小。我们的研究结果表明 CYP2C8 参与了人类伊马替尼的代谢，并且支持肠内摄取转运体参与了伊马替尼的吸收。
