Key result
Metronidazole significantly augmented mean warfarin levels and hypoprothrombinemia when co-administered with racemic and S(-)-warfarin (P<0.01), but no interaction occurred with R(+)-warfarin.
Why the study?
Does metronidazole stereoselectively alter the plasma levels and hypoprothrombinemic effects of warfarin enantiomers in normal subjects?
Does metronidazole stereoselectively alter the plasma levels and hypoprothrombinemic effects of warfarin enantiomers in normal subjects?
p-value: p=<0.01
The drug interaction between metronidazole and warfarin is stereoselective, affecting only the S(-)-enantiomer, suggesting that R(+)-warfarin could be used to avoid this interaction.
Alerts to stereoselective metronidazole-warfarin interaction requiring INR monitoring; leaves open enantiomer-specific strategies pending patient studies.
Because of the known interaction of warfarin and disulfiram and the "disulfiram effect" of metronidazole, the interaction with metronidazole of commercial racemic warfarin and its separated enantiomorphs was evaluated in eight normal subjects. Single oral doses of racemate, S(-)-warfarin, and R (+)-warfarin, were administered in the amounts of 1.5, 0.75 and 1.5 mg per kilogram of body weight, respectively, with and without metronidazole, 750 mg by mouth, beginning seven days before the warfarin dose and continuing seven days before the warfarin dose and continuing daily throughout the hypoprothrombinemia. Daily plasma samples were analyzed for warfarin in content and one-stage prothrombin time. A highly significant (P less than 0.01) augmentation of the mean warfarin level and hypoprothrombinemia with metronidazole occurred for racemic and S (-)-warfarin; none occurred with R (+)-warfarin. Thus, the interaction of racemic warfarin and metronidazole is stereoselective and can be lessened or even avoided by use of R (+)-warfarin alone for long-term therapy.
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Robert A. O’Reilly (1976) studied Healthy volunteers (n=8). Metronidazole vs. Without metronidazole was evaluated on Mean warfarin level and hypoprothrombinemia (p=<0.01). Metronidazole significantly augmented mean warfarin levels and hypoprothrombinemia when co-administered with racemic and S(-)-warfarin (P<0.01), but no interaction occurred with R(+)-warfarin.
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