Shin Jae-Gook, Kang Won-Ku, Shon Ji-Hong, Arefayene Million, Yoon Young-Ran, Kim Kyung-Ah, Kim Doo-Il, Kim Dong-Soo, Cho Kwang-Hyun, Woosley Raymond L, Flockhart David A
Department of Pharmacology and Pharmacogenomics Research Centre, Inje University College of Medicine, Busan, Korea.
Br J Clin Pharmacol. 2007 Feb;63(2):206-15. doi: 10.1111/j.1365-2125.2006.02793.x. Epub 2006 Nov 10.
The aim of this study was to evaluate the pharmacokinetics and pharmacodynamics of quinidine-induced QT prolongation in healthy Caucasian and Korean subjects to investigate interethnic differences in susceptibility to drug-induced arrhythmia.
A randomized, double-blind crossover study was conducted in 24 (12 male and 12 female) Korean and 13 (seven male and six female) Caucasian subjects. After a 20 min infusion of quinidine (4 mg kg(-1)) or saline, the serum concentration of quinidine and the QT interval corrected by Bazett's formula (QTc) were monitored. The dynamic data were analyzed by means of a population modelling approach using NONMEM.
There were no statistical differences in the pharmacokinetic profiles of quinidine between ethnic groups. The QTc values in Caucasians were higher than those in Koreans at the same quinidine concentrations, especially at higher quinidine concentrations and in female subjects. According to an E(max) model [equation: see text], the population modelling approach revealed that E0 (ms) was related to gender (408 + [34*(1 - Sex)]; 1 for male and 0 for female), DeltaE(max) (ms) was related to ethnicity ((136*f(ETHN)) + C(female): f(ETHN) = 1 for Koreans and 1.26 for Caucasians; C(female) was 106 only for Caucasian females), and EC50 was estimated to be 3.13 microm.
These results suggest that Korean subjects were less sensitive to quinidine-induced QT prolongation than Caucasian subjects, and that this trend was particularly true for females. Further population-based studies are merited to characterize more completely the ethnic differences in drug-induced QT prolongation between Asians and other ethnic groups.
本研究旨在评估奎尼丁在健康白种人和韩国受试者中诱导QT间期延长的药代动力学和药效学，以研究药物诱导性心律失常易感性的种族间差异。
对24名（12名男性和12名女性）韩国受试者和13名（7名男性和6名女性）白种人受试者进行了一项随机、双盲交叉研究。在输注奎尼丁（4mg/kg）或生理盐水20分钟后，监测奎尼丁的血清浓度以及用Bazett公式校正的QT间期（QTc）。使用NONMEM通过群体建模方法分析动态数据。
不同种族间奎尼丁的药代动力学特征无统计学差异。在相同的奎尼丁浓度下，尤其是在较高奎尼丁浓度时以及女性受试者中，白种人的QTc值高于韩国人。根据E(max)模型[公式：见正文]，群体建模方法显示E0（毫秒）与性别有关（408 + [34*(1 - 性别)]；男性为1，女性为0），ΔE(max)（毫秒）与种族有关（(136*f(ETHN)) + C(女性)：f(ETHN)，韩国人为1，白种人为1.26；C(女性)仅对白种人女性为106），并且估计EC50为3.13微摩尔。
这些结果表明，韩国受试者对奎尼丁诱导的QT间期延长的敏感性低于白种人受试者，并且这种趋势在女性中尤为明显。值得进行更多基于群体的研究，以更全面地表征亚洲人和其他种族之间药物诱导的QT间期延长的种族差异。
