POLYMORPHISM OF PROPAFENONE METABOLISM AND DISPOSITION IN MAN - CLINICAL AND PHARMACOKINETIC CONSEQUENCES
POLYMORPHISM OF PROPAFENONE METABOLISM AND DISPOSITION IN MAN - CLINICAL AND PHARMACOKINETIC CONSEQUENCES
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DOI：
10.1161/01.cir.75.4.785
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发表时间：
1987-04-01
期刊：
影响因子：
37.8
通讯作者：
WOOSLEY, RL
中科院分区：
文献类型：
--
作者：
SIDDOWAY, LA;THOMPSON, KA;WOOSLEY, RL
对28例慢性室性心律失常患者（22例异喹胍强代谢型，6例异喹胍弱代谢型）进行异喹胍代谢表型与普罗帕酮药代动力学和药效学的关系研究。EM的特征是普罗帕酮消除半衰期较短（5.5 ±. 2.1相对于17.2 .+-。8.0，p < .001），较低的平均血浆浓度（Cp）（1.1 . ±. 0.6相对于2.5 .+-。0.5 ng/ml/mg日剂量，p <0.001）和较高的口服清除率（1115 ± 0.001）。1238对264 .+-. 48 ml/min，p < .001）。活性代谢物5-羟基普罗帕酮，在12例患者中进行了分析，确定在9个10 EM，但在两个PM。在EM中注意到中枢神经系统副作用的发生率较低（14%对67%，p <0.01）。在任何给定的普罗帕酮Cp下，EM的QRS增宽幅度大于PM。EMs和PMs在普罗帕酮有效剂量和抗心律失常反应频率方面无显著差异。普罗帕酮对异喹胍4-羟基化的抑制作用在体内和体外人肝微粒体系统中均得到证实。我们的结论是，普罗帕酮是通过相同的细胞色素P-450负责异喹的4-羟基化代谢，其药代动力学和浓度-反应关系和中枢神经系统副作用的发生率是不同的异喹代谢表型的患者不同。
The relationship between debrisoquine metabolic phenotype and the pharmacokinetics and pharmacodynamics of propafenone was studied in 28 patients with chronic ventricular arrhythmias (22 extensive metabolizers [EMs] and six poor metabolizers [PMs] of debrisoquine). EMs were characterized by a shorter propafenone elimination half-life (5.5 .+-. 2.1 vs 17.2 .+-. 8.0, p < .001), lower average plasma concentration (Cp) (1.1 .+-. 0.6 vs 2.5 .+-. 0.5 ng/ml/mg daily dosage, p < .001), and higher oral clearance (1115 .+-. 1238 vs 264 .+-. 48 ml/min, p < .001). The active metabolite 5-hydroxypropafenone, assayed in 12 patients, was identified in nine of 10 EMs but in neither of the PMs. A lower incidence of central nervous system side effects was noted in EMs (14% vs 67%, p < .01). The magnitude of QRS widening at any given propafenone Cp was greater in EMs than PMs. There was no significant difference between EMs and PMs in effective propafenone dose or frequency of antiarrhythmic response. Inhibition of debrisoquine 4-hydroxylation by propafenone was demonstrated both in vivo and in a human liver microsomal system in vitro. We conclude that propafenone is metabolized via the same cytochrome P-450 responsible for debrisoquine''s 4-hydroxylation, and that its pharmacokinetics and concentration-response relationships and the incidence of central nervous system side effects are different in patients of different debrisoquine metabolic phenotype.