Related Experiment Videos
Effect of miconazole on warfarin disposition in rabbits
A P D'Mello1, R V Venkataramanan, T R Bates
1Department of Pharmaceutics, Philadelphia College of Pharmacy and Science, PA 19104.
Abstract:
To elucidate the mechanism underlying the reported potentiation of warfarin anticoagulant action after initiation of miconazole therapy, the effects of acute and chronic miconazole administration on warfarin disposition were examined in six adult New Zealand male rabbits. The rabbits received a 3.5 mg/kg iv dose of warfarin either alone, 1 hr after a single 100 mg/kg ip miconazole dose, or on day 5 of a 6-day 50 mg/kg/12 hr ip miconazole dosing regimen. Acute miconazole administration decreased the elimination rate constant of warfarin, but other warfarin disposition parameters were not altered. Chronic miconazole administration caused a 47% increase in warfarin plasma-free fraction (probably caused by competitive or noncompetitive protein binding displacement by miconazole metabolites) and a 42% decrease in warfarin intrinsic clearance (probably caused by a miconazole-induced inhibition in warfarin metabolism). As a consequence of these quantitatively similar but opposite changes, the total body clearance of warfarin (a low clearance drug) was marginally decreased. A significant decrease in the elimination rate constant and an increase in the tissue-free fraction of warfarin were also observed during chronic miconazole treatment. These results suggest that chronic miconazole administration should not significantly affect the steady-state plasma concentrations of total warfarin, but should increase the steady-state plasma concentrations of free warfarin. The expected increases in the steady-state plasma concentrations of free, pharmacologically active warfarin may account for the reported potentiation of the pharmacological action of warfarin when coadministered with chronic miconazole. Measurement of total plasma concentrations, and estimation of total body clearance might be misleading, and inadequate in identifying certain drug interactions involving low clearance drugs.
Insights
Chronic miconazole therapy increases free warfarin levels by affecting protein binding and metabolism, potentially explaining enhanced anticoagulant effects. Total warfarin levels may not reflect this interaction in low clearance drugs.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Drug Interactions
- Anticoagulant Therapy
Background:
- Miconazole therapy is known to potentiate warfarin's anticoagulant action.
- The precise mechanism behind this drug interaction remains incompletely understood.
- Warfarin is a widely prescribed anticoagulant with a narrow therapeutic index.
Purpose of the Study:
- To investigate the pharmacokinetic effects of acute and chronic miconazole administration on warfarin disposition in rabbits.
- To elucidate the mechanism by which miconazole influences warfarin's anticoagulant activity.
Main Methods:
- Six adult male New Zealand rabbits were administered warfarin intravenously.
- Warfarin was given alone, after acute miconazole, or after chronic miconazole dosing.
- Warfarin disposition parameters, including plasma-free fraction and intrinsic clearance, were analyzed.
Main Results:
- Acute miconazole marginally decreased warfarin's elimination rate constant.
- Chronic miconazole significantly increased warfarin's plasma-free fraction and decreased its intrinsic clearance.
- These changes led to a marginal decrease in total body clearance but an increase in free warfarin concentrations.
Conclusions:
- Chronic miconazole administration increases free, active warfarin concentrations, likely accounting for potentiated anticoagulant effects.
- Measuring total warfarin plasma concentrations may be insufficient to assess this drug interaction.
- Understanding these pharmacokinetic alterations is crucial for managing patients on combined warfarin and miconazole therapy.