Salazar D E, Much D R, Nichola P S, Seibold J R, Shindler D, Slugg P H
Department of Clinical Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
J Clin Pharmacol. 1997 Sep;37(9):799-809. doi: 10.1002/j.1552-4604.1997.tb05627.x.
The objective of this study was to assess the pharmacokinetics and pharmacodynamics of the dextro (d-) isomer of sotalol, a class III antiarrhythmic agent, in healthy young men and women after a single intravenous bolus dose. The design was open-label, randomized, parallel group. Each group (4 men and 4 women) received either 0.5, 1.5, or 3.0 mg/kg d-sotalol as an intravenous infusion for 2 minutes. Serial measurements of the d-sotalol plasma concentration and the Q-Tc interval data were recorded before, during, and for 72 hours after drug administration. The pharmacokinetics of d-sotalol were found to be well described by a three-compartment model with linear elimination clearance from the central compartment. There were no significant differences in the elimination clearance or volume of the central compartment between dose levels or between men and women. However, women were found to have a lower steady-state volume of distribution than men (1.20 L/Kg versus 1.43 L/Kg). The Q-Tc versus d-sotalol plasma concentration data were fitted to a model that assumed a distinct "effect compartment" and sigmoidal Emax response. The baseline Q-Tc, determined from the fittings, was found to be significantly higher in women (0.40 versus 0.38 seconds). The effect compartment clearance was found to be highly variable, with a median of 12.3 (range, 0.2-671,300) L/h. There were statistically significant differences in the effect compartment clearance by dose among men and by gender at a dose of 1.5 mg/kg. There were no significant differences detected between dose groups or genders for the d-sotalol effect site concentration at one half the maximum Q-Tc prolongation from baseline (EC50), EMAX, (the maximum Q-Tc prolongation from baseline) or the Hill coefficient. In conclusion, the pharmacokinetics of d-sotalol after intravenous administration are independent of dose and gender, because the difference between men and women in volume of distribution at steady-state is not clinically significant. The pharmacodynamics of Q-Tc prolongation produced by d-sotalol appear to be independent of dose and gender; however, there is considerable variability in the time course of effects on Q-Tc between individuals.
本研究的目的是评估Ⅲ类抗心律失常药物索他洛尔右旋（d-）异构体在健康青年男性和女性单次静脉推注给药后的药代动力学和药效学。研究设计为开放标签、随机、平行组。每组（4名男性和4名女性）接受0.5、1.5或3.0mg/kg的d-索他洛尔静脉输注2分钟。在给药前、给药期间以及给药后72小时记录d-索他洛尔血浆浓度和Q-Tc间期数据的系列测量值。发现d-索他洛尔的药代动力学可用三室模型很好地描述，从中央室线性消除清除率。剂量水平之间或男性与女性之间在消除清除率或中央室容积方面无显著差异。然而，发现女性的稳态分布容积低于男性（1.20L/Kg对1.43L/Kg）。将Q-Tc与d-索他洛尔血浆浓度数据拟合到一个假设存在独特“效应室”和S形Emax反应的模型。根据拟合确定的基线Q-Tc在女性中显著更高（0.40对0.38秒）。发现效应室清除率高度可变，中位数为12.3（范围，0.2 - 671,300）L/h。在1.5mg/kg剂量下，男性之间以及按性别在效应室清除率方面存在统计学显著差异。在从基线最大Q-Tc延长的一半（EC50）、EMAX（从基线的最大Q-Tc延长）或希尔系数方面，剂量组或性别之间在d-索他洛尔效应部位浓度上未检测到显著差异。总之，静脉给药后d-索他洛尔的药代动力学与剂量和性别无关，因为男性与女性在稳态分布容积上的差异无临床意义。d-索他洛尔引起的Q-Tc延长的药效学似乎与剂量和性别无关；然而，个体之间对Q-Tc的效应时间过程存在相当大的变异性。
