Usefulness of coadministration of bucolome in warfarin therapy: pharmacokinetic and pharmacodynamic analysis using outpatient prescriptions.

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.