Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
Clin Pharmacol Ther. 2012 May;91(5):846-55. doi: 10.1038/clpt.2011.313.
Therapeutic doses of gemfibrozil cause mechanism-based inactivation of CYP2C8 via formation of gemfibrozil 1-O-β-glucuronide. We investigated the extent of CYP2C8 inactivation caused by three different doses of gemfibrozil twice dailyfor 5 days, using repaglinide as a probe drug, in 10 healthy volunteers. At the end of this 5-day regimen, there were dose-dependent increases in the area under the plasma concentration–time curve from 0 to infinity (AUC0–∞) of repaglinide by3.4-, 5.5-, and 7.0-fold corresponding to 30, 100, and 600 mg of gemfibrozil, respectively, as compared with the control phase (P < 0.001). On the basis of a mechanism-based inactivation model involving gemfibrozil 1-O-β-glucuronide, a gemfibrozil dose of 30 mg twice daily was estimated to inhibit CYP2C8 by >70% and 100 mg twice daily was estimated to inhibit it by >90%. Hence, gemfibrozil is a strong inactivator of CYP2C8 even in very small, subtherapeutic, multiple doses. Administration of small gemfibrozil doses may be useful in optimizing the pharmacokinetics of CYP2C8 substrate drugs and in reducing the formation of their potentially toxic metabolites via CYP2C8.
吉非贝齐的治疗剂量会通过形成吉非贝齐 1-O-β-葡糖苷酸而导致 CYP2C8 的基于机制的失活。我们用瑞格列奈作为探针药物，在 10 位健康志愿者中研究了每天两次服用 3 种不同剂量的吉非贝齐 5 天对 CYP2C8 失活的程度。在这个 5 天疗程结束时，与对照阶段相比，瑞格列奈的血浆浓度-时间曲线下面积（AUC0-∞）分别增加了 3.4 倍、5.5 倍和 7.0 倍，相应地为 30、100 和 600 mg 吉非贝齐（P < 0.001）。基于涉及吉非贝齐 1-O-β-葡糖苷酸的基于机制的失活模型，每天两次服用 30 mg 吉非贝齐估计会抑制 CYP2C8 的活性超过 70%，每天两次服用 100 mg 吉非贝齐估计会抑制其活性超过 90%。因此，吉非贝齐即使在非常小的、亚治疗剂量下，也是 CYP2C8 的强抑制剂。给予小剂量的吉非贝齐可能有助于优化 CYP2C8 底物药物的药代动力学，并通过 CYP2C8 减少其潜在毒性代谢物的形成。
