华法林和阿司匹林联用在大鼠体内的药代动力学研究

目的: 探讨华法林和阿司匹林联用在大鼠体内非稳态和稳态条件下的药代动力学相互作用的规律,为临床合理药物联用提供依据。方法: 将大鼠随机分为3组,即华法林组(0.2 mg/kg),阿司匹林组(10 mg/kg),华法林(0.2 mg/kg)＋阿司匹林组(10 mg/kg)联用组,每组6只,给大鼠灌胃,连续 6 d,在第1天和第6天多个时间点取样,分析和比较非稳态和稳态下血药浓度时间曲线和药代动力学参数。结果: 华法林药动学用二室模型描述,阿司匹林药动学用一室模型描述。在非稳态和稳态下,阿司匹林单用和联用的血药浓度-时间曲线相似,药代动力学参数之间均无统计学差异;在非稳态下,华法林单用和联用的血药浓度-时间曲线也类似,但在稳态下,联用的血药浓度时间曲线明显高于单用时的曲线,药代动力学计算结果也表明联用时的AUC和C_max较单用时较大,且有统计意义。结论: 当华法林和阿司匹林联用达到稳态时,阿司匹林对华法林的药动学参数有影响,增大了华法林的暴露(AUC和C_max)。提示两药联用时,很可能增大患者的出血风险,临床上药物联用时应该注意。

Pharmacokinetic interaction between warfarin and aspirin in rats

AIM: To explore the pharmacokinetic interaction between warfarin and aspirin in rats at non-steady-state and steady-state.METHODS: Three groups of six rats each were used according to a parallel study. Group I (warfarin) received daily repeated 0.2 mg/kg intragastric administration. Group II (aspirin) received daily repeated 10 mg/kg intragastric administration. Group III (warfarin plus aspirin) was administered as drug combination, namely daily oral dose of 0.2 mg/kg warfarin and 10 mg/kg aspirin. The rats received once daily repeated oral administration for 6 days. Plasma drug concentrations were obtained at scheduled time points on the first and the 6th day after dosing. The pharmacokinetic profiles and calculated parameters were analyzed and compared.RESULTS: The pharmacokinetics of warfarin and aspirin were best fitted to a two-compartment and one compartment model, respectively. At non-steady-state, the concentration-time course and related parameters of warfarin and aspirin was not changed by each other. At steady-state, the pharmacokinetic characteristics of warfarin were also not changed by aspirin. However, after multiple doses, Aspirin increased the peak plasma concentration and area under the curve of warfarin at steady-state.CONCLUSION: At steady-state after multiple dosing, aspirin increased the exposure of warfarin, which indicates that the combination therapy may increase the bleeding risk. This increase may represent a safety concern. The results suggest some differences of pharmacokinetic properties between warfarin and aspirin combinations at steady state, which indicates that when warfarin and aspirin are administered together, therapeutic drug monitoring should be enhanced.