Osawa Makiko, Hada Nobuko, Matsumoto Kaori, Hasegawa Tetsuya, Kobayashi Daisuke, Morimoto Yasunori, Yamaguchi Masatoshi, Kanamoto Ikuo, Nakagawa Teruaki, Sugibayashi Kenji
Department of Pharmacy, Sekishinkai Sayama Hospital, 1-33 Unoki, Sayama, Saitama 350-1323, Japan.
Int J Pharm. 2005 Apr 11;293(1-2):43-9. doi: 10.1016/j.ijpharm.2004.12.009.
Bucolome, a nonsteroidal anti-inflammatory drug, has often been coadministered to patients who take warfarin as an anticoagulant. This combination increases the anticoagulant effect, which is most likely due to the interaction of bucolome with the pharmacokinetics (PK) or pharmacodynamics (PD) of warfarin. More than 30 years ago the mechanism of this interaction was reported to be inhibition of warfarin protein binding by bucolome, and the inhibition of warfarin metabolism by bucolome was also recently reported. Here, we examined daily doses of warfarin and its anticoagulant effect (thrombo-test, TT) in outpatient prescriptions in five hospitals to elucidate the drug interaction and the usefulness of this drug combination. Among the warfarin prescriptions, 78 were for patients also taking bucolome and 99 were for patients not taking bucolome. The daily dose of warfarin in patients taking bucolome was significantly lower than those without bucolome (ca. 40%). TT in patients taking bucolome was significantly lower as compared to those not taking bucolome. Control of the anticoagulant effect was greater with coadministration of bucolome and warfarin than with warfarin alone. PK and PD analysis of our results suggests that the improved therapeutic effect resulting from coadministration of warfarin with bucolome was due to lower and less patient-to-patient variation of intrinsic hepatic clearance (CL(int)) of warfarin, since bucolome decreased the high CL(int) but did not have a great effect on the low CL(int). In conclusion, administration of bucolome in warfarin therapy is useful to control the anticoagulant effect of warfarin. Attention should also be paid to the enzymatic inhibition by bucolome on the PK of coadministered drugs.
布可隆，一种非甾体抗炎药，常与服用华法林作为抗凝剂的患者合用。这种联合用药会增强抗凝效果，这很可能是由于布可隆与华法林的药代动力学（PK）或药效动力学（PD）相互作用所致。30多年前，据报道这种相互作用的机制是布可隆抑制华法林的蛋白结合，最近也有报道称布可隆抑制华法林的代谢。在此，我们研究了五家医院门诊处方中华法林的每日剂量及其抗凝效果（血栓试验，TT），以阐明药物相互作用以及这种药物组合的效用。在华法林处方中，78例是给同时服用布可隆的患者，99例是给未服用布可隆的患者。服用布可隆的患者华法林每日剂量显著低于未服用布可隆的患者（约40%）。与未服用布可隆的患者相比，服用布可隆的患者TT显著更低。布可隆与华法林合用对抗凝效果的控制比单独使用华法林更好。对我们结果的PK和PD分析表明，华法林与布可隆合用产生的治疗效果改善是由于华法林肝脏内在清除率（CL(int)）的患者间差异更低且更小，因为布可隆降低了高CL(int)，但对低CL(int)没有太大影响。总之，在华法林治疗中使用布可隆有助于控制华法林的抗凝效果。还应注意布可隆对合用药物PK的酶抑制作用。
