Ziviani L, Da Ros L, Squassante L, Milleri S, Cugola M, Iavarone L E
Glaxo Wellcome, Medicine Research Centre, Verona, Italy.
Br J Clin Pharmacol. 2001 Feb;51(2):147-52. doi: 10.1111/j.1365-2125.2001.bcp119.x.
Lacidipine, a long acting 2, 4-dihydropyridine calcium channel antagonist is frequently administered with cholesterol lowering agents, particularly in elderly populations. The effects of lacidipine on the pharmacokinetics of simvastatin were investigated, since they share the CYP3A4 pathway for metabolism.
The study was an open, randomised, two-way crossover design, with at least 7 days washout. Eighteen healthy subjects received simvastatin, 40 mg once daily, alone and together with lacidipine, 4 mg once daily, for 8 days. The pharmacokinetics of simvastatin were studied on the eighth day. Analysis was made of total simvastatin acid concentrations (naive simvastatin acid plus that derived from alkaline hydrolysis of the lactone).
Lacidipine increased the maximum concentration of simvastatin (Cmax) by approximately 70% (P=0.016) and the area under the plasma concentration-time curve AUC(0,24 h) by approximately 35% (P=0.001). The mean Cmax and AUC(0,24 h) of simvastatin (95% confidence interval) when given alone were 8.76 (6.72-11.41) ng ml(-1) and 60.36 (47.15-77.28) ng ml(-1) h. During treatment with lacidipine they were, respectively, 14.89 (10.77-20.58) ng ml(-1) and 80.96 (64.62-101.44) ng ml(-1) h. No significant differences were observed in either time to peak concentration (tmax was 1.0 h for simvastatin alone and 1.5 h for the combination) or in the half-life (t1/2,z was 8.5 h in both cases). The combination was safe and well tolerated.
The observed increased exposure to simvastatin 40 mg following coadministration of lacidipine is unlikely to be of clinical relevance.
拉西地平是一种长效的2,4-二氢吡啶类钙通道拮抗剂，常与降胆固醇药物联用，尤其在老年人群中。由于辛伐他汀和拉西地平共享CYP3A4代谢途径，因此研究了拉西地平对辛伐他汀药代动力学的影响。
本研究采用开放、随机、双向交叉设计，洗脱期至少7天。18名健康受试者分别接受辛伐他汀（每日一次，40毫克）单独给药，以及与拉西地平（每日一次，4毫克）联合给药，各持续8天。在第8天研究辛伐他汀的药代动力学。分析了辛伐他汀酸的总浓度（天然辛伐他汀酸加上由内酯碱性水解产生的辛伐他汀酸）。
拉西地平使辛伐他汀的最大浓度（Cmax）增加了约70%（P = 0.016），血浆浓度-时间曲线下面积AUC(0,24 h)增加了约35%（P = 0.001）。辛伐他汀单独给药时的平均Cmax和AUC(0,24 h)（95%置信区间）分别为8.76（6.72 - 11.41）纳克/毫升和60.36（47.15 - 77.28）纳克/毫升·小时。在与拉西地平联合治疗期间，它们分别为14.89（10.77 - 20.58）纳克/毫升和80.96（64.62 - 101.44）纳克/毫升·小时。在达峰时间（辛伐他汀单独给药时tmax为1.0小时，联合给药时为1.5小时）或半衰期（两种情况下t1/2,z均为8.5小时）方面均未观察到显著差异。联合用药安全且耐受性良好。
拉西地平与40毫克辛伐他汀联合给药后观察到的辛伐他汀暴露增加不太可能具有临床相关性。
