Markert Christoph, Kastner Ida Maria, Hellwig Regina, Kalafut Peter, Schweizer Yvonne, Hoffmann Michael Marcus, Burhenne Jürgen, Weiss Johanna, Mikus Gerd, Haefeli Walter Emil
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
Basic Clin Pharmacol Toxicol. 2015 May;116(5):423-8. doi: 10.1111/bcpt.12332. Epub 2014 Nov 8.
To evaluate the impact of CYP2C19 polymorphisms on ambrisentan exposure and to assess its modification by St. John's wort (SJW), 20 healthy volunteers (10 CYP2C19 extensive, four poor and six ultrarapid metabolizers) received therapeutic doses of ambrisentan (5 mg qd po) for 20 days and concomitantly SJW (300 mg tid po) for the last 10 days. To quantify changes of CYP3A4 activity, midazolam (3 mg po) as a probe drug was used. Ambrisentan pharmacokinetics was assessed on days 1, 10 and 20, and midazolam pharmacokinetics before and on days 1, 10, 17 and 20. At steady state, ambrisentan exposure was similar in extensive and ultrarapid metabolizers but 43% larger in poor metabolizers (p < 0.01). In all volunteers, SJW reduced ambrisentan exposure and the relative change (17-26%) was similar in all genotype groups. The extent of this interaction did not correlate with the changes in CYP3A activity (midazolam clearance) (rs = 0.23, p = 0.34). Ambrisentan had no effect on midazolam pharmacokinetics. In conclusion, SJW significantly reduced exposure with ambrisentan irrespective of the CYP2C19 genotype. The extent of this interaction was small and thus likely without clinical relevance.
为评估CYP2C19基因多态性对安立生坦暴露量的影响，并评估圣约翰草（SJW）对其的修饰作用，20名健康志愿者（10名CYP2C19基因广泛代谢者、4名慢代谢者和6名超快代谢者）接受了治疗剂量的安立生坦（5mg口服，每日一次），持续20天，并在最后10天同时服用SJW（300mg口服，每日三次）。为量化CYP3A4活性的变化，使用咪达唑仑（3mg口服）作为探针药物。在第1、10和20天评估安立生坦的药代动力学，在第1、10、17和20天以及之前评估咪达唑仑的药代动力学。在稳态时，安立生坦在广泛代谢者和超快代谢者中的暴露量相似，但在慢代谢者中高出43%（p<0.01）。在所有志愿者中，SJW降低了安立生坦的暴露量，所有基因型组的相对变化（17 - 26%）相似。这种相互作用的程度与CYP3A活性（咪达唑仑清除率）的变化不相关（rs = 0.23，p = 0.34）。安立生坦对咪达唑仑的药代动力学没有影响。总之，无论CYP2C19基因型如何，SJW均显著降低了安立生坦的暴露量。这种相互作用的程度较小，因此可能无临床意义。
