Prueksaritanont T, Vega J M, Rogers J D, Gagliano K, Greenberg H E, Gillen L, Brucker M J, McLoughlin D, Wong P H, Waldman S A
Merck Research Laboratories, Blue Bell, Pennsylvania, USA.
J Clin Pharmacol. 2000 Nov;40(11):1274-9.
Potential for inhibition of CYP3A activity by simvastatin, an HMG-CoA reductase inhibitor, was evaluated in 12 healthy male subjects who received placebo or 80 mg of simvastatin, the maximal recommended dose, once daily for 7 consecutive days. On day 7, an intravenous injection of 3 microCi [14C N-methyl]erythromycin for the erythromycin breath test (EBT) was coadministered with a 2 mg oral solution of midazolam. The values for percent 14C exhaled during the first hour (for EBT) and the pharmacokinetic parameters of midazolam (AUC, Cmax, t1/2) were not affected following multiple once-daily oral doses of simvastatin 80 mg. The 95% confidence interval was 0.97 to 1.18 for EBT and 0.99 to 1.23 for midazolam AUC. In addition, the total urinary recoveries of midazolam and its 1'-hydroxy metabolites (free plus conjugate) obtained from both treatments were not statistically different (p > 0.200). These data demonstrate that multiple dosing of simvastatin, at the highest recommended clinical dose, does not significantly alter the in vivo hepatic or intestinal CYP3A4/5 activity as measured by the commonly used EBT and oral midazolam probes.
在12名健康男性受试者中评估了HMG-CoA还原酶抑制剂辛伐他汀对CYP3A活性的抑制潜力。这些受试者连续7天每天接受一次安慰剂或80mg辛伐他汀（最大推荐剂量）。在第7天，静脉注射3微居里[14C N-甲基]红霉素用于红霉素呼气试验（EBT），并同时给予2mg咪达唑仑口服溶液。多次每日口服80mg辛伐他汀后，第一小时呼出的14C百分比（用于EBT）以及咪达唑仑的药代动力学参数（AUC、Cmax、t1/2）未受影响。EBT的95%置信区间为0.97至1.18，咪达唑仑AUC的95%置信区间为0.99至1.23。此外，两种治疗方法获得的咪达唑仑及其1'-羟基代谢物（游离加结合物）的总尿回收率无统计学差异（p>0.200）。这些数据表明，以最高推荐临床剂量多次服用辛伐他汀，并不会如常用的EBT和口服咪达唑仑探针所测量的那样，显著改变体内肝脏或肠道的CYP3A4/5活性。
