Le A T, Hasson N K, Lum B L
University of the Pacific, School of Pharmacy, Montara, CA 94037, USA.
Ann Pharmacother. 1997 Sep;31(9):1006-8. doi: 10.1177/106002809703100910.
To report a case of a possible drug interaction between warfarin, carboplatin, and etoposide resulting in a marked increase in a patient's response to warfarin, and to outline monitoring strategies for this interaction.
A 74-year-old white man receiving warfarin (average dose 42.5 mg/wk) for atrial fibrillation was diagnosed with a right testicular non-seminoma mixed germ cell tumor. Mediastinal metastases were subsequently discovered, and the patient was treated with a chemotherapy regimen including carboplatin and etoposide. Sixteen days after the first course of chemotherapy, the international normalized ratio (INR) was increased to 12.6 from a baseline range of 1.15-2.11 that was observed over the previous 8 months of therapy, indicating a clinically significant alteration in the pharmacodynamic response to warfarin.
This patient had no concomitant disease or dietary changes to explain the altered response to warfarin. Carboplatin and etoposide have not been reported to inhibit warfarin metabolism. However, previous reports have suggested that etoposide may displace warfarin from its protein binding sites, resulting in an early elevation in prothrombin time following chemotherapy. The late elevation of INR observed in our patient suggests that his response to warfarin may have been due to the displacement of warfarin by elemental platinum, which has a long plasma half-life.
This case report suggests a possible drug interaction between carboplatin, etoposide, and warfarin. Because of the risk associated with an increased response to warfarin, we recommend close monitoring of the INR, perhaps twice weekly, early and later in the time course following chemotherapy with these agents. Appropriate dosage adjustments of warfarin should be performed if an altered response to warfarin is observed.
报告一例华法林、卡铂和依托泊苷之间可能存在药物相互作用导致患者对华法林反应显著增强的病例，并概述针对这种相互作用的监测策略。
一名74岁白人男性因心房颤动接受华法林治疗（平均剂量42.5毫克/周），被诊断为右睾丸非精原细胞瘤混合性生殖细胞肿瘤。随后发现纵隔转移，该患者接受了包括卡铂和依托泊苷的化疗方案。在第一个化疗疗程后的第16天，国际标准化比值（INR）从之前8个月治疗期间观察到的1.15 - 2.11的基线范围升至12.6，表明对华法林的药效学反应发生了具有临床意义的改变。
该患者没有伴随疾病或饮食变化来解释对华法林反应的改变。尚未有报道称卡铂和依托泊苷会抑制华法林代谢。然而，先前的报告表明依托泊苷可能会将华法林从其蛋白质结合位点置换出来，导致化疗后凝血酶原时间早期升高。在我们的患者中观察到的INR后期升高表明，他对华法林的反应可能是由于具有较长血浆半衰期的元素铂将华法林置换所致。
本病例报告提示卡铂、依托泊苷和华法林之间可能存在药物相互作用。由于存在对华法林反应增强相关的风险，我们建议在使用这些药物进行化疗的过程中，早期和后期密切监测INR，可能每周两次。如果观察到对华法林的反应发生改变，应适当调整华法林剂量。
