Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital of Heidelberg, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Eur J Clin Pharmacol. 2013 Oct;69(10):1785-93. doi: 10.1007/s00228-013-1529-1. Epub 2013 Jun 9.
We assessed the effect of cytochrome P450 (CYP) 3A4 and the OATP1B1 inhibitor clarithromycin on ambrisentan steady-state kinetics and its relationship to the SLCO1B1 15 haplotype in healthy volunteers.
In this open-label, monocenter, one-sequence crossover clinical trial ten male healthy participants were stratified according to CYP2C19 and SLCO1B1 (encoding for OATP1B1) genotype into two groups: group 1 (n = 6), with CYP2C19 1/1 (extensive metabolizer, EM) and SLCO1B1 wild-type; group 2 (n = 4), with CYP2C19 EM and homozygous (n = 3) or heterozygous for SLCO1B1 15 (n = 1). The participants were administered a once-daily oral dose of 5 mg ambrisentan on study days 1 and days 3-14 and twice-daily oral doses of 500 mg clarithromycin on study days 11-14. To monitor CYP3A activity 3 mg midazolam was given orally 1 day before the first ambrisentan administration and on days 1, 10, and 14 of ambrisentan treatment. Ambrisentan plasma kinetics was assessed on days 1 (single dose), 10 (steady-state), and 14 (CYP3A4/OATP1B1 inhibition by clarithromycin).
Consistent with the expectation that ambrisentan does not induce its own metabolism, ambrisentan exposure and peak concentration (Cmax) were similar after the first dose and at steady-state. Clarithromycin increased the area under the plasma concentration-time curve of ambrisentan by 41 % and Cmax by 27 % (n = 10, both p < 0.05). No contribution of SLCO1B1*15 to the extent of this interaction was observed.
Clarithromycin increased ambrisentan exposure to a similar extent to ketoconazole, namely, clinically minor and likely irrelevant.
我们评估细胞色素 P450（CYP）3A4 和 OATP1B1 抑制剂克拉霉素对安贝生坦稳态药代动力学的影响及其与健康志愿者 SLCO1B1 15 单倍型的关系。
在这项开放标签、单中心、单序列交叉临床试验中，根据 CYP2C19 和 SLCO1B1（编码 OATP1B1）基因型，将 10 名男性健康受试者分层为两组：组 1（n=6），CYP2C19 1/1（广泛代谢者，EM）和 SLCO1B1 野生型；组 2（n=4），CYP2C19 EM 且纯合子（n=3）或杂合子 SLCO1B1 15（n=1）。第 1 天和第 3-14 天，受试者每天口服一次 5mg 安贝生坦，第 11-14 天每天口服两次 500mg 克拉霉素。为了监测 CYP3A 活性，在第一次给予安贝生坦前 1 天和安贝生坦治疗的第 1、10 和 14 天，口服 3mg 咪达唑仑。在第 1 天（单次剂量）、第 10 天（稳态）和第 14 天（克拉霉素抑制 CYP3A4/OATP1B1）评估安贝生坦的血浆药代动力学。
与安贝生坦不诱导自身代谢的预期一致，首次给药后和稳态时，安贝生坦的暴露量和峰浓度（Cmax）相似。克拉霉素使安贝生坦的血浆浓度-时间曲线下面积增加 41%，Cmax 增加 27%（n=10，均 p<0.05）。未观察到 SLCO1B1*15 对这种相互作用程度的贡献。
克拉霉素使安贝生坦的暴露量增加到与酮康唑相似的程度，即临床意义较小且可能无关紧要。
