College of Pharmacy & Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.
J Pharm Pharmacol. 2013 Aug;65(8):1195-203. doi: 10.1111/jphp.12084. Epub 2013 May 28.
This study aimed to evaluate the effects of torsemide on warfarin therapy in humans and rats.
For the animal study, rats were orally dosed with warfarin (0.13 mg/kg, control group) or warfarin (0.13 mg/kg) with torsemide (2 mg/kg, low dose group and 10 mg/kg, high dose group). The pharmacodynamic response of warfarin was assessed by measuring the international normalized ratio (INR) for 5 consecutive days following drug administration. For the human study, 191 patients on warfarin with mechanical heart valves were followed up retrospectively. The stable dose was calculated as the mean dose in INR levels of 2-3 for 3 consecutive times.
In the animal study, the INR, maximum plasma concentration (Cmax ) and area under the plasma drug concentration-time curve (AUC0-∞ ) of (S)-warfarin in the high dose group were significantly higher than in other groups (P < 0.05). Compared with the control group, Cmax and AUC0-∞ of (R)-warfarin in the high and low dose groups were higher, whereas the volume of distribution/bioavailability and clearance/bioavailability were significantly lower (P < 0.05). In the univariate analysis of the clinical study, diuretics significantly lowered stable warfarin doses (P = 0.016) (5.07 ± 1.78 mg/day vs 5.77 ± 1.81 mg/day). After controlling confounding variables, the effects of diuretics were found to lower the warfarin dose by 0.464 mg.
It was concluded that warfarin dose needs to be lowered when it is used concomitantly with diuretics.
本研究旨在评估托塞米对人体和大鼠华法林治疗的影响。
在动物研究中，大鼠分别给予华法林（0.13mg/kg，对照组）或华法林（0.13mg/kg）加托塞米（低剂量组 2mg/kg 和高剂量组 10mg/kg）口服给药。通过连续 5 天测量国际标准化比值（INR）来评估华法林的药效反应。在人体研究中，对 191 例服用华法林的机械心脏瓣膜患者进行了回顾性随访。稳定剂量计算为 INR 水平为 2-3 时连续 3 次的平均剂量。
在动物研究中，高剂量组（S）-华法林的 INR、最大血浆浓度（Cmax）和血浆药物浓度-时间曲线下面积（AUC0-∞）明显高于其他组（P<0.05）。与对照组相比，高剂量组和低剂量组（R）-华法林的 Cmax 和 AUC0-∞更高，而分布体积/生物利用度和清除率/生物利用度显著降低（P<0.05）。在临床研究的单变量分析中，利尿剂显著降低了稳定的华法林剂量（P=0.016）（5.07±1.78mg/天 vs 5.77±1.81mg/天）。在控制混杂变量后，利尿剂对华法林剂量的影响被发现降低了 0.464mg。
结论是当华法林与利尿剂同时使用时，需要降低华法林的剂量。
