Mörike K E, Roden D M
Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37232-6602.
Clin Pharmacol Ther. 1994 Jan;55(1):28-34. doi: 10.1038/clpt.1994.6.
Propafenone, a sodium channel blocking antiarrhythmic drug with beta-blocking properties, is metabolized to non-beta-blocking metabolites in part by cytochrome P4502D6. Subtherapeutic doses of quinidine inhibit P4502D6 and increase plasma propafenone in extensive metabolizer subjects, in whom the active enzyme is present. In this study we tested the hypothesis that quinidine would enhance beta-blockade in extensive metabolizers receiving propafenone. Seven extensive and two poor metabolizers received propafenone (225 mg orally every 8 hours) plus quinidine sulfate (60 mg orally every 8 hours) or propafenone plus placebo for 7 days in a randomized, double-blind, crossover fashion. In extensive metabolizers, the coadministration of quinidine significantly increased the extent of propafenone-induced beta-blockade, assessed by a decrease in exercise heart rate and by sensitivity to isoproterenol. We conclude that low-dose quinidine enhances propafenone-induced beta-blockade in extensive metabolizers. Thus the polymorphic patterns of drug metabolism can result in clinically significant drug interactions on a genetic basis.
普罗帕酮是一种具有β受体阻滞特性的钠通道阻滞剂类抗心律失常药物，部分通过细胞色素P4502D6代谢为无β受体阻滞作用的代谢产物。亚治疗剂量的奎尼丁可抑制P4502D6，并使有活性酶存在的快代谢型受试者的血浆普罗帕酮水平升高。在本研究中，我们检验了奎尼丁会增强接受普罗帕酮治疗的快代谢型患者的β受体阻滞作用这一假设。7名快代谢型受试者和2名慢代谢型受试者以随机、双盲、交叉方式接受普罗帕酮（每8小时口服225 mg）加硫酸奎尼丁（每8小时口服60 mg）或普罗帕酮加安慰剂治疗7天。在快代谢型受试者中，联合应用奎尼丁显著增强了普罗帕酮诱导的β受体阻滞作用，这通过运动心率降低和对异丙肾上腺素的敏感性来评估。我们得出结论，低剂量奎尼丁可增强快代谢型受试者中普罗帕酮诱导的β受体阻滞作用。因此，药物代谢的多态性模式可在遗传基础上导致具有临床意义的药物相互作用。
