2017 年 43 巻 6 号 p. 297-305
Due to its interaction with many anticancer drugs, warfarin has a diverse mechanism of action, such as inhibition of cytochrome P450 (CYP) 2C9, protein binding replacement, lower absorption of vitamin K due to gut toxicity, and so forth. We experienced a case in which sunitinib, a molecular-targeted agent, was administered while undergoing warfarin, and the international normalized ratio of prothrombin time (PT-INR) increased remarkably. Here, we investigate the pharmacological mechanism of PT-INR increase in this patient both experimentally and in the literature. A 67-year-old man was stable with PT-INR (2.0-2.3) using warfarin for anticoagulation. A cancerous pleural effusion from renal cell carcinoma was observed, and sunitinib was started. Immediately after taking sunitinib, warfarin was reduced because PT-INR was elevated, but PT-INR increased further to 6.12 on Day 10 after sunitinib initiation. In in vitro experiments, sunitinib did not inhibit CYP2C9 at clinical concentrations. In this patient, sunitinib concentration was not changed under warfarin combination. Sunitinib shows a protein binding rate of < 95％, and since he had hypoalbuminemia, protein binding substitution may induce an increase in unbound warfarin. However, from the viewpoint of plasma concentrations of both drugs, protein binding substitution could not contribute to this interaction. It also suggests the contribution of insufficient intake and absorption of vitamin K owing to sunitinib-induced anorexia and gastrointestinal disturbances. Furthermore, the contribution of disseminated intravascular coagulation was indicated, as the D-dimer was high. Despite this case, careful monitoring of PT-INR is necessary when sunitinib and warfarin are combined, as the mechanism is not fully understood.
