Tornio Aleksi, Neuvonen Pertti J, Backman Janne T
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Eur J Clin Pharmacol. 2006 Aug;62(8):645-51. doi: 10.1007/s00228-006-0155-6. Epub 2006 Jul 11.
Zopiclone is a short acting hypnotic, which is metabolised by cytochrome P450 (CYP) 3A4 and 2C8 in vitro. We studied the possible effect of gemfibrozil, an inhibitor of CYP2C8, on the pharmacokinetics and pharmacodynamics of zopiclone.
In a randomised 2-phase crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 3 days. On day 3, each ingested a 7.5 mg dose of zopiclone. Plasma concentrations and urinary excretion of zopiclone and its two primary metabolites, plasma gemfibrozil, and psychomotor performance were measured. The effects of CYP2C8, CYP2C9 and CYP3A4 inhibitors on the depletion of zopiclone (500 nM) were studied in vitro in human liver microsomes.
The pharmacokinetic variables of the parent zopiclone were not significantly affected by gemfibrozil. However, gemfibrozil raised the mean peak plasma concentration (C(max)) of N-oxide-zopiclone (1.6-fold; P<0.001) and that of N-desmethyl-zopiclone (1.2-fold; P<0.001). The mean area under the plasma concentration-time curve (AUC(0)-infinity) values of N-oxide-zopiclone and N-desmethyl-zopiclone were raised 2-fold (P<0.001) and 1.2-fold (P<0.01), respectively. The renal clearance of N-oxide-zopiclone was reduced by 48% by gemfibrozil (P<0.001). The pharmacodynamic effects of zopiclone, measured using psychometric tests, were not affected by gemfibrozil. In vitro, ketoconazole (1 microM) and itraconazole (8 microM) decreased the elimination rate of zopiclone enantiomers by about 65-95%, while montelukast (16 microM), gemfibrozil (200 microM) and sulfaphenazole (10 microM) had no appreciable effect.
Gemfibrozil does not increase the plasma concentrations of the parent zopiclone. Accordingly, CYP2C8 does not significantly metabolise zopiclone in vivo. However, as gemfibrozil raises the concentrations of two potentially active metabolites of zopiclone, slightly enhanced effects of zopiclone by gemfibrozil can not be excluded.
佐匹克隆是一种短效催眠药，在体外由细胞色素P450（CYP）3A4和2C8代谢。我们研究了CYP2C8抑制剂吉非贝齐对佐匹克隆药代动力学和药效学的可能影响。
在一项随机双阶段交叉研究中，10名健康志愿者每日口服600 mg吉非贝齐或安慰剂，分两次服用，共3天。在第3天，每人服用7.5 mg佐匹克隆剂量。测定佐匹克隆及其两种主要代谢物的血浆浓度和尿排泄量、血浆吉非贝齐浓度以及精神运动表现。在人肝微粒体中体外研究了CYP2C8、CYP2C9和CYP3A4抑制剂对佐匹克隆（500 nM）消耗的影响。
吉非贝齐对母体佐匹克隆的药代动力学变量无显著影响。然而，吉非贝齐使N-氧化佐匹克隆的平均血浆峰浓度（C(max)）升高（1.6倍；P<0.001），使N-去甲基佐匹克隆的平均血浆峰浓度升高（1.2倍；P<0.001）。N-氧化佐匹克隆和N-去甲基佐匹克隆的血浆浓度-时间曲线下平均面积（AUC(0)-无穷大）值分别升高2倍（P<0.001）和1.2倍（P<0.01）。吉非贝齐使N-氧化佐匹克隆的肾清除率降低48%（P<0.001）。使用心理测量测试测定的佐匹克隆药效学效应不受吉非贝齐影响。在体外，酮康唑（1 microM）和伊曲康唑（8 microM）使佐匹克隆对映体的消除率降低约65-95%，而孟鲁司特（16 microM）、吉非贝齐（200 microM）和磺胺苯吡唑（10 microM）没有明显影响。
吉非贝齐不会增加母体佐匹克隆的血浆浓度。因此，CYP2C8在体内对佐匹克隆的代谢作用不显著。然而，由于吉非贝齐提高了佐匹克隆两种潜在活性代谢物的浓度，不能排除吉非贝齐使佐匹克隆作用略有增强的可能性。
