College of Pharmacy and Center for Pharmacogenomics, University of Florida, Health Science Center, Gainesville, FL 32610-0486, USA.
Pharmacotherapy. 2011 Oct;31(10):942-50. doi: 10.1592/phco.31.10.942.
Abstract Study Objective. To assess the effects of the cytochrome P450 (CYP) 3A genotype, CYP3A5, on atorvastatin pharmacokinetics and its interaction with clarithromycin. Design. Prospective, two-phase, randomized-sequence, open-label pharmacokinetic study. Setting. Clinical research center at a teaching hospital. Subjects. Twenty-three healthy volunteers who were screened for genotype: 10 subjects carried the CYP3A5*1 allele (expressors) and 13 subjects did not (nonexpressors). Intervention. In one phase, subjects received a single oral dose of atorvastatin 20 mg. In the other phase, subjects received clarithromycin 500 mg twice/day for 5 days; on day 4 after the morning dose, subjects also received a single oral dose of atorvastatin 20 mg. All subjects participated in both phases of the study, which were separated by at least 14 days. Measurements and Main Results. Pharmacokinetic parameters of both forms of atorvastatin-atorvastatin acid and atorvastatin lactone-were compared between CYP3A5 expressors and nonexpressors, both in the absence and presence of clarithromycin, a strong CYP3A inhibitor. The acid form is pharmacologically active, and the lactone form has been associated with the atorvastatin's muscle-related adverse effects. Atorvastatin acid exposure did not differ significantly between CYP3A5 genotype groups. When subjects had not received clarithromycin pretreatment, the area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-∞)) of atorvastatin lactone was 36% higher in nonexpressors than in expressors (median 47.6 ng•hr/ml [interquartile range (IQR) 37.8-64.3 ng•hr/ml] vs 34.9 ng•hr/ml [IQR 21.6-42.2 ng•hr/ml], p=0.038). After clarithromycin pretreatment, changes in the pharmacokinetic parameters of atorvastatin acid and lactone were not significantly different between the nonexpressors versus the expressors; however, the increase in the AUC(0-∞) of atorvastatin lactone was 37% greater in expressors than in nonexpressors (geometric mean ± SD 3.59 ± 0.57 vs 2.62 ± 0.35, p=0.049). Conclusion. Our data suggest that the CYP3A5 genotype has minimal effects on the pharmacokinetic parameters of atorvastatin and its interaction with clarithromycin; these effects are unlikely to be clinically significant.
摘要 研究目的：评估细胞色素 P450（CYP）3A 基因型（CYP3A5）对阿托伐他汀药代动力学的影响及其与克拉霉素的相互作用。 设计：前瞻性、两阶段、随机序列、开放标签药代动力学研究。 地点：教学医院的临床研究中心。 受试者：23 名健康志愿者，经基因筛查确定 CYP3A51 等位基因：10 名受试者携带 CYP3A51 等位基因（表达者），13 名受试者未携带该等位基因（非表达者）。 干预：在一个阶段，受试者接受单剂量 20mg 阿托伐他汀口服给药。在另一个阶段，受试者接受克拉霉素 500mg 每日 2 次，共 5 天；在第 4 天早晨剂量后，受试者还接受单剂量 20mg 阿托伐他汀口服给药。所有受试者均参加了研究的两个阶段，两个阶段之间至少间隔 14 天。 测量和主要结果：在无克拉霉素和有克拉霉素（一种强 CYP3A 抑制剂）的情况下，比较了 CYP3A5 表达者和非表达者两种阿托伐他汀-阿托伐他汀酸和阿托伐他汀内酯形式的药代动力学参数。酸形式具有药理活性，内酯形式与阿托伐他汀的肌肉相关不良反应有关。阿托伐他汀酸暴露在 CYP3A5 基因型组之间无显著差异。当受试者未接受克拉霉素预处理时，非表达者的阿托伐他汀内酯的浓度-时间曲线下面积从零时间外推至无穷大（AUC（0-∞））比表达者高 36%（中位数 47.6ng·hr/ml[四分位距（IQR）37.8-64.3ng·hr/ml]比 34.9ng·hr/ml[IQR 21.6-42.2ng·hr/ml]，p=0.038）。在克拉霉素预处理后，非表达者与表达者之间阿托伐他汀酸和内酯的药代动力学参数变化无显著差异；然而，表达者的阿托伐他汀内酯 AUC（0-∞）增加了 37%（几何均数±标准差 3.59±0.57 比 2.62±0.35，p=0.049）。 结论：我们的数据表明，CYP3A5 基因型对阿托伐他汀的药代动力学参数及其与克拉霉素的相互作用影响很小；这些影响不太可能具有临床意义。
