Kantola T, Kivistö K T, Neuvonen P J
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Eur J Clin Pharmacol. 1999 Jan;54(11):851-5. doi: 10.1007/s002280050566.
To determine the effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of cerivastatin, a competitive 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor.
A randomized, double-blind, cross-over study design with two phases, which were separated by a washout period of 4 weeks, was used. In each phase ten healthy volunteers took 200 mg itraconazole or matched placebo orally once daily for 4 days according to a randomization schedule. On day 4, 0.3 mg cerivastatin was administered orally. Serum concentrations of cerivastatin, its major metabolites, active and total HMG-CoA reductase inhibitors, itraconazole and hydroxyitraconazole were measured up to 24 h.
Itraconazole increased the area under the concentration-time curve from time zero to infinity (AUC(0-infinity)) of the parent cerivastatin by 15% (P < 0.05). The mean peak serum concentration (Cmax) of cerivastatin lactone was increased 1.8-fold (range 1.1-fold to 2.4-fold, P < 0.001) and the AUC(0-24h) 2.6-fold (range 2.0-fold to 3.6-fold, P < 0.001) by itraconazole. The elimination half-life (t1/2) of cerivastatin lactone was increased 3.2-fold (P < 0.001). Itraconazole decreased the AUC(0-24h) of the active M-1 metabolite of cerivastatin by 28% (P < 0.05), whereas the AUC(0- 24h) of the more active metabolite, M-23, was increased by 36% (P < 0.05). The AUC(0-24h) and t1/2 of active HMG-CoA reductase inhibitors were increased by 27% (P < 0.05) and 40% (P < 0.05), respectively, by itraconazole.
Itraconazole has a modest interaction with cerivastatin. Inhibition of the CYP3A4-mediated M-1 metabolic pathway leads to elevated serum concentrations of cerivastatin, cerivastatin lactone and metabolite M-23, resulting in increased concentrations of active HMG-CoA reductase inhibitors.
确定强效细胞色素P450 3A4（CYP3A4）抑制剂伊曲康唑对竞争性3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂西立伐他汀药代动力学的影响。
采用随机、双盲、两阶段交叉研究设计，两阶段之间有4周的洗脱期。在每个阶段，10名健康志愿者根据随机方案每天口服200mg伊曲康唑或匹配的安慰剂，共4天。在第4天，口服0.3mg西立伐他汀。测定西立伐他汀及其主要代谢产物、活性和总HMG-CoA还原酶抑制剂、伊曲康唑和羟基伊曲康唑的血清浓度，持续24小时。
伊曲康唑使母体西立伐他汀从零时间到无穷大的浓度-时间曲线下面积（AUC(0-∞)）增加了15%（P<0.05）。伊曲康唑使西立伐他汀内酯的平均血清峰浓度（Cmax）增加了1.8倍（范围为1.1倍至2.4倍，P<0.001），AUC(0-24h)增加了2.6倍（范围为2.0倍至3.6倍，P<0.001）。西立伐他汀内酯的消除半衰期（t1/2）增加了3.2倍（P<0.001）。伊曲康唑使西立伐他汀活性M-1代谢产物的AUC(0-24h)降低了28%（P<0.05），而活性更高的代谢产物M-23的AUC(0-24h)增加了36%（P<0.05）。伊曲康唑使活性HMG-CoA还原酶抑制剂的AUC(0-24h)和t1/2分别增加了27%（P<0.05）和40%（P<0.05）。
伊曲康唑与西立伐他汀存在适度相互作用。抑制CYP3A4介导的M-1代谢途径导致西立伐他汀、西立伐他汀内酯和代谢产物M-23的血清浓度升高，从而使活性HMG-CoA还原酶抑制剂的浓度增加。
