Knoell K R, Young T M, Cousins E S
College of Pharmacy, Ohio State University, Columbus, OH, USA.
Ann Pharmacother. 1998 Dec;32(12):1299-302. doi: 10.1345/aph.17456.
To report an unexpected decrease in warfarin effect following the addition of ritonavir to the medication regimen.
A 27-year-old patient with advanced HIV taking warfarin for an inferior vena cava thrombus was started on ritonavir, clarithromycin, and zidovudine. The international normalized ratio (INR) decreased over a period of weeks after the addition of ritonavir, clarithromycin, and zidovudine to the drug therapy regimen. The warfarin dosage was almost doubled in order to maintain a therapeutic INR. Months later, when ritonavir alone was discontinued, the INR rose rapidly and the warfarin dose requirements decreased significantly.
Potential interactions between warfarin and the protease inhibitors are described in the literature. Ritonavir has been shown to be a potent inhibitor of CYP3A4, an enzyme responsible for warfarin metabolism. Potentiation of warfarin effect and subsequent decrease in the warfarin dosage requirement was anticipated following ritonavir administration; however, the opposite occurred. The mechanism of the potential interaction between warfarin and ritonavir is not known, and may represent a complex, multidrug interaction. The paradoxical decrease in the INR is particularly intriguing.
Frequent, careful monitoring of warfarin is recommended when ritonavir therapy is initiated or discontinued in a patient taking warfarin. The potential for either an increase or decrease in the INR should be anticipated.
报告在药物治疗方案中添加利托那韦后华法林疗效意外降低的情况。
一名27岁晚期HIV患者因下腔静脉血栓服用华法林，开始接受利托那韦、克拉霉素和齐多夫定治疗。在药物治疗方案中添加利托那韦、克拉霉素和齐多夫定后的几周内，国际标准化比值（INR）下降。为维持治疗性INR，华法林剂量几乎加倍。数月后，仅停用利托那韦时，INR迅速上升，华法林剂量需求显著降低。
文献中描述了华法林与蛋白酶抑制剂之间的潜在相互作用。利托那韦已被证明是细胞色素P450 3A4（CYP3A4，一种负责华法林代谢的酶）的强效抑制剂。预计服用利托那韦后华法林疗效会增强，随后华法林剂量需求会降低；然而，实际情况却相反。华法林与利托那韦之间潜在相互作用的机制尚不清楚，可能代表一种复杂的多药相互作用。INR出现反常降低尤其令人费解。
对于正在服用华法林的患者，开始或停止使用利托那韦治疗时，建议频繁、仔细地监测华法林。应预计到INR可能升高或降低。
