Inhibition of (S)-warfarin metabolism by sulfinpyrazone and its metabolites.
Sulfinpyrazone markedly potentiates the anticoagulant effect of warfarin. The increased clotting time is accompanied by a marked decrease in the clearance of (S)-warfarin by virtue of a decrease in the P4502C9-catalyzed formation clearance to its major and inactive metabolite (S)-7-hydroxywarfarin. These data suggested that the mechanism of the drug interaction might be mediated through the inhibition of the catalytic activity of P4502C9 by sulfinpyrazone. However, initial human liver microsomal studies indicated that the in vitro Ki, for inhibition of (S)-7-hydroxywarfarin formation by sulfinpyrazone is at least 25-fold higher than the therapeutic concentration of sulfinpyrazone in vivo. This result implied that other inhibitors probably contribute to the interaction. Kinetic studies conducted on sulfinpyrazone and two major metabolites, sulfinpyrazone sulfide and sulfinpyrazone sulfone, in microsomes prepared from three human livers give mean Ki's of 230 microM, 17 microM, and 73 microM respectively. Because sulfinpyrazone and its sulfide metabolite attain comparable plasma concentrations during the course of therapy, our inhibition results suggest that the sulfide metabolite is likely to be the primary species responsible for the inhibition of P4502C9-catalyzed formation of (S)-7-hydroxywarfarin and the decrease in (S)-warfarin clearance in vivo.
He
M
M
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195, USA.
Kunze
K L
KL
Trager
W F
WF
D004357:Drug Synergism; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013440:Sulfides / Q000494:pharmacology; D013442:Sulfinpyrazone / Q000378:metabolism* / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D014859:Warfarin / Q000378:metabolism* / Q000493:pharmacokinetics
D013440:Sulfides; D013450:Sulfones; D014859:Warfarin; D013442:Sulfinpyrazone