Kantola T, Kivistö K T, Neuvonen P J
Department of Clinical Pharmacology, University of Helsinki, and the Helsinki University Central Hospital, Finland.
Clin Pharmacol Ther. 1998 Aug;64(2):177-82. doi: 10.1016/S0009-9236(98)90151-5.
To study the effects of erythromycin and verapamil on the pharmacokinetics of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
A randomized, double-blind crossover study was performed with three phases separated by a washout period of 3 weeks. Twelve young, healthy volunteers took orally either 1.5 gm/day erythromycin, 240 mg/day verapamil, or placebo for 2 days. On day 2, 40 mg simvastatin was administered orally. Serum concentrations of simvastatin, simvastatin acid, erythromycin, verapamil, and norverapamil were measured for up to 24 hours.
Erythromycin and verapamil increased mean peak serum concentration (Cmax) of unchanged simvastatin 3.4-fold (p < 0.001) and 2.6-fold (p < 0.05) and the area under the serum simvastatin concentration-time curve from time zero to 24 hours [AUC(0-24)] 6.2-fold (p < 0.001) and 4.6-fold (p < 0.01). Erythromycin increased the mean Cmax of active simvastatin acid fivefold (p < 0.001) and the AUC(0-24) 3.9-fold (p < 0.001). Verapamil increased the Cmax of simvastatin acid 3.4-fold (p < 0.001) and the AUC(0-24) 2.8-fold (p < 0.001). There was more than tenfold interindividual variability in the extent of simvastatin interaction with both erythromycin and verapamil.
Both erythromycin and verapamil interact considerably with simvastatin, probably by inhibiting its cytochrome P450 (CYP) 3A4-mediated metabolism. Concomitant administration of erythromycin, verapamil, or other potent inhibitors of CYP3A4 with simvastatin should be avoided. As an alternative, the dosage of simvastatin should be reduced considerably, that is, by about 50% to 80%, at least when a simvastatin dosage higher than 20 mg/day is used. Possible adverse effects, such as elevation of creatine kinase level and muscle tenderness, should be closely monitored when such combinations are used.
研究红霉素和维拉帕米对3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂辛伐他汀药代动力学的影响。
进行一项随机、双盲交叉研究，分三个阶段，各阶段间隔3周的洗脱期。12名年轻健康志愿者口服1.5克/天红霉素、240毫克/天维拉帕米或安慰剂，为期2天。在第2天，口服40毫克辛伐他汀。测定辛伐他汀、辛伐他汀酸、红霉素、维拉帕米和去甲维拉帕米的血清浓度，最长测定24小时。
红霉素和维拉帕米使未代谢的辛伐他汀平均血清峰浓度（Cmax）分别升高3.4倍（p<0.001）和2.6倍（p<0.05），使血清辛伐他汀浓度-时间曲线从零至24小时的曲线下面积[AUC(0-24)]分别升高6.2倍（p<0.001）和4.6倍（p<0.01）。红霉素使活性辛伐他汀酸的平均Cmax升高5倍（p<0.001），AUC(0-24)升高3.9倍（p<0.001）。维拉帕米使辛伐他汀酸的Cmax升高3.4倍（p<0.001），AUC(0-24)升高2.8倍（p<0.001）。辛伐他汀与红霉素和维拉帕米相互作用程度的个体间差异超过10倍。
红霉素和维拉帕米均与辛伐他汀有显著相互作用，可能是通过抑制其细胞色素P450（CYP）3A4介导的代谢。应避免辛伐他汀与红霉素、维拉帕米或其他强效CYP3A4抑制剂合用。作为替代方法，至少在使用高于20毫克/天的辛伐他汀剂量时，应将辛伐他汀剂量大幅降低，即降低约50%至80%。使用此类联合用药时，应密切监测可能的不良反应，如肌酸激酶水平升高和肌肉压痛。
