Department of Pharmaceutical Technology and Biopharmaceutics, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania.
Clin Drug Investig. 2012 Aug 1;32(8):533-8. doi: 10.1007/BF03261904.
Phenytoin is an inductor of the main metabolizing enzyme of ivabradine and it could influence its pharmacokinetics. Changes in ivabradine pharmacokinetics could have clinical significance regarding the safety of the treatment.
The study objective was evaluation of the pharmacokinetic interaction between ivabradine and phenytoin in healthy subjects.
A single dose of ivabradine 10 mg was administered alone or in combination with phenytoin 150 mg to 18 healthy subjects in a two-treatment study design, separated by 5 days in which the phenytoin alone was administered at a dose of 150 mg twice daily. Plasma concentrations of ivabradine were determined during a 12-hour period following drug administration, using a high-throughput liquid chromatography coupled with mass spectrometry analytical method. Pharmacokinetic parameters of ivabradine administered in each treatment were calculated using non-compartmental analysis and compared to determine if the differences were statistically significant.
In the two treatment periods, the mean ± SD peak plasma concentrations (C(max)) were 18.6 ± 8.0 ng/mL (ivabradine alone) and 6.5 ± 3.1 ng/mL (ivabradine after pre-treatment with phenytoin). The mean ± SD times taken to reach C(max) (t(max)) were 1.2 ± 0.7 h and 0.8 ± 0.6 h, respectively, and the total areas under the plasma concentration-time curve from time zero to infinity (AUC(∞)) were 62.3 ± 18.7 ng · h/mL and 19.2 ± 17.0 ng · h/mL, respectively. Statistically significant differences were observed for the C(max) and AUC(∞) of ivabradine when administered alone or with phenytoin, whereas for t(max) and the half-life the differences were non-significant.
This study showed that phenytoin has an important effect on the pharmacokinetics of ivabradine in healthy subjects, reducing its bioavailability by approximately 70%.
苯妥英是伊伐布雷定主要代谢酶的诱导剂，可能会影响其药代动力学。伊伐布雷定药代动力学的变化可能对治疗的安全性具有重要的临床意义。
本研究旨在评估健康受试者中伊伐布雷定与苯妥英之间的药代动力学相互作用。
采用两治疗期交叉设计，18 名健康受试者单次口服伊伐布雷定 10mg 单药或联合苯妥英 150mg（每天两次，每次 150mg），两治疗期之间间隔 5 天。采用高效液相色谱-串联质谱法测定给药后 12 小时内伊伐布雷定的血药浓度。采用非房室模型分析方法计算各治疗期伊伐布雷定的药代动力学参数，并比较差异是否具有统计学意义。
在两治疗期，伊伐布雷定的平均（±SD）峰浓度（Cmax）分别为 18.6±8.0ng/ml（伊伐布雷定单药）和 6.5±3.1ng/ml（伊伐布雷定与苯妥英合用）。达峰时间（tmax）分别为 1.2±0.7h 和 0.8±0.6h，0 到无穷时的药时曲线下面积（AUC∞）分别为 62.3±18.7ng·h/ml 和 19.2±17.0ng·h/ml。与伊伐布雷定单药相比，合用苯妥英时，伊伐布雷定的 Cmax 和 AUC∞差异有统计学意义，而 tmax 和半衰期差异无统计学意义。
本研究表明，苯妥英对健康受试者伊伐布雷定的药代动力学有重要影响，使伊伐布雷定的生物利用度降低约 70%。
