Pharmacokinetic and pharmacodynamic interactions of aspirin with warfarin in beagle dogs

Abstract

1. Warfarin and aspirin are widely used in a wide spectrum of thromboembolic and atherothrombotic diseases. Despite the potential efficacy of warfarin–aspirin therapy, the safety and side effect of combined therapy remains unclear.

2. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic interactions between warfarin and aspirin in beagles after single and multiple doses.

3. Coadministration of aspirin had no significant effects on the area under the plasma concentration time curve (AUC_0–t) and maximum plasma concentration (C_max) of R- and S-warfarin after a single dose of warfarin, but significantly increase the AUC_0–t and C_max and dramatically decrease the clearance (CL) of R- and S-warfarin after multiple dose of warfarin. Accordingly, there was a slight increase in the AUEC_0–t and E_max of activated partial thromboplastin time (aPTT), prothrombin time (PT) and international normalized ratio (INR) after multiple dose of warfarin.

4. Coadministration of warfarin had no markedly effects on the AUC_0–t and C_max of aspirin and its metabolite salicylic acid after single or multiple dose of aspirin. Meanwhile, the AUEC_0–t and E_max of inhibition of platelet aggregation (IPA) were not significantly affected by warfarin.

5. Our animal study indicated that coadministration of aspirin with warfarin can cause significant pharmacokinetic and pharmacodynamic drug–drug interactions in beagles. However, more studies are urgently needed to assess related information of warfarin–aspirin drug interactions in healthy volunteers or patients.

• Aspirin
• drug–drug interaction
• pharmacodynamics
• pharmacokinetic
• R- and S-warfarin
• salicylic acid