Neuvonen P J, Kantola T, Kivistö K T
Department of Clinical Pharmacology, University of Helsinki, Finland.
Clin Pharmacol Ther. 1998 Mar;63(3):332-41. doi: 10.1016/S0009-9236(98)90165-5.
Itraconazole increases the risk of skeletal muscle toxicity of some 3-hydroxy-3-methylglutaryl coenzyme A' (HMG-CoA) reductase inhibitors by increasing their serum concentrations. We studied possible interactions of itraconazole with simvastatin and pravastatin.
Two randomized, double-blind, two-phase crossover studies were performed with use of an identical design, one with simvastatin (study I) and one with pravastatin (study II). In both studies, 10 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of simvastatin (study I) or pravastatin (study II). Serum concentrations of simvastatin, simvastatin acid, pravastatin, HMG-CoA reductase inhibitors, itraconazole, and hydroxyitraconazole were determined.
In study I, itraconazole increased the peak serum concentrations (Cmax) and the areas under the serum concentration-time curve [AUC(0-infinity)] of simvastatin and simvastatin acid at least tenfold (p < 0.001). The Cmax and AUC(0-infinity) of total simvastatin acid (naive simvastatin acid plus that derived by hydrolysis of the lactone) were increased 17-fold and 19-fold (p < 0.001), respectively, and the half-life (t1/2) was increased by 25% (p < 0.05). The AUC(0-infinity) of HMG-CoA reductase inhibitors was increased fivefold (p < 0.001) and the Cmax and t1/2 were increased threefold (p < 0.001). In study II, itraconazole slightly increased the AUC(0-infinity) and Cmax of pravastatin, but the changes were statistically nonsignificant (p = 0.052 and 0.172, respectively). The t1/2 was not altered. The AUC(0-infinity) and Cmax of HMG-CoA reductase inhibitors were increased less than twofold (p < 0.05 and p = 0.063, respectively) by itraconazole. There were no differences in the serum concentrations of itraconazole and hydroxyitraconazole between studies I and II.
Itraconazole greatly increased serum concentrations of simvastatin, simvastatin acid, and HMG CoA reductase inhibitors, probably by inhibiting CYP3A-mediated metabolism, but it had only a minor effect on pravastatin. Concomitant use of potent inhibitors of CYP3A with simvastatin should be avoided or its dosage should be greatly reduced.
伊曲康唑通过提高某些3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂的血清浓度，增加了其骨骼肌毒性风险。我们研究了伊曲康唑与辛伐他汀和普伐他汀之间可能的相互作用。
采用相同设计进行了两项随机、双盲、两阶段交叉研究，一项针对辛伐他汀（研究I），另一项针对普伐他汀（研究II）。在两项研究中，10名健康志愿者每天口服一次200mg伊曲康唑或安慰剂，共4天。在第4天，每位受试者服用单剂量40mg的辛伐他汀（研究I）或普伐他汀（研究II）。测定了辛伐他汀、辛伐他汀酸、普伐他汀、HMG-CoA还原酶抑制剂、伊曲康唑和羟基伊曲康唑的血清浓度。
在研究I中，伊曲康唑使辛伐他汀和辛伐他汀酸的血清峰值浓度（Cmax）以及血清浓度-时间曲线下面积[AUC(0-∞)]至少增加了10倍（p<0.001）。总辛伐他汀酸（天然辛伐他汀酸加上内酯水解产生的辛伐他汀酸）的Cmax和AUC(0-∞)分别增加了17倍和19倍（p<0.001），半衰期（t1/2）增加了25%（p<0.05）。HMG-CoA还原酶抑制剂的AUC(0-∞)增加了5倍（p<0.001），Cmax和t1/2增加了3倍（p<0.001）。在研究II中，伊曲康唑使普伐他汀的AUC(0-∞)和Cmax略有增加，但变化无统计学意义（分别为p=0.052和0.172）。t1/2未改变。伊曲康唑使HMG-CoA还原酶抑制剂的AUC(0-∞)和Cmax增加不到2倍（分别为p<0.05和p=0.063）。研究I和研究II中伊曲康唑和羟基伊曲康唑的血清浓度无差异。
伊曲康唑可能通过抑制CYP3A介导的代谢，大大提高了辛伐他汀、辛伐他汀酸和HMG-CoA还原酶抑制剂的血清浓度，但对普伐他汀的影响较小。应避免将CYP3A的强效抑制剂与辛伐他汀同时使用，或应大幅降低其剂量。
