Pharmacokinetic interaction between warfarin and a uricosuric agent, bucolome: Application of in vitro approaches to predicting in vivo reduction of (S)-warfarin clearance

A uricosuric agent, bucolome, has been shown to intensify the anticoagulant effect of warfarin. The aims of the present study were to clarify its mech anism(s) and to apply in vitro approaches for predicting this potentially l ife-threatening in vivo interaction. An in vivo study revealed that Japanes e patients given warfarin with bucolome (300 mg/day, n = 21) showed a 1.5-f old greater international normalized ratio than those given warfarin alone (n = 34) despite that the former received a 58% smaller warfarin dose than the latter. Enantioselective assays revealed that bucolome increased plasma unbound fractions of (S)- and (R)-warfarin by 2-fold (p < .01), reduced un bound oral clearances of (S)- and (R)- warfarin by 84 (p < .01) and 26% (p < .05), respectively, and inhibited the unbound formation clearance for (S) -warfarin 7-hydroxylation by 89% (p < .01). In contrast, bucolome elicited no appreciable changes in the plasma unbound (S)- warfarin concentration ve rsus the international normalized ratio relationship. In vitro studies with recombinant human cytochrome P-450 2C9 and liver microsomes showed that bu colome was a potent mixed-type inhibitor for (S)-warfarin 7-hydroxylation, with K-i of 8.2 and 20.2 mu M, respectively. An in vitro model incorporatin g maximum unbound bucolome concentration in the liver estimated as a sum of hepatic artery and portal vein concentrations and in vitro K-i made an acc eptable prediction for bucolome-induced reductions in in vivo total (bound + unbound) oral clearance, unbound oral clearance, and unbound formation cl earance for (S)-warfarin. In conclusion, the augmented anticoagulant effect of warfarin by bucolome due to the metabolic inhibition for pharmacologica lly more potent (S)- warfarin may be predictable from in vitro data.