The aim of this study was to develop and validate a safe and sensitive in vivo model for the detection of potential warfarin-drug interactions in man. A single 25mg dose of racemic warfarin was administered to 18 consenting healthy male volunteers on day 4 of a randomised 7-day multiple dose regimen with one of the following treatments: vitamin K1 (10mg once daily in the evening), cholestyramine (4g three times daily before meals), rifampicin (600mg once daily in the morning), cimetidine (400mg twice daily), aspirin (600mg twice daily) or placebo (1 lactose capsule once daily in the morning). A total of 17 blood samples were obtained at predetermined intervals from 0 to 96 hours after warfarin ingestion for determination of prothrombin time, clotting factors II, VII and X, and total plasma warfarin concentration. The interacting agents produced clearly discernible effects on warfarin dynamics: attenuated by cholestyramine and rifampicin, potentiated by aspirin and cimetidine, and practically abolished by vitamin K1. The area under the plasma warfarin concentration-time curve was decreased by the presence of aspirin, rifampicin and cholestyramine, and increased by cimetidine.
The model described appears to satisfy the criteria for detecting a potential clinically significant in vivo warfarin-drug interaction in healthy volunteers; the mechanism of such an interaction may be subsequently investigated using other methodology.
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Duursema, L., Müller, F.O., Hundt, H.K.L. et al. Model to Detect Warfarin-Drug Interactions in Man. Drug Invest 4, 395–402 (1992). https://doi.org/10.1007/BF03258417
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