Piperine Alters the Pharmacokinetics and Anticoagulation of Warfarin in Rats

Abstract

Introduction: Piperine, the bioactive compound of black pepper, and warfarin are metabolized by cytochrome P450 enzymes and are both highly plasma protein-bound compounds. In this study, we evaluated the effect of co-administered piperine on the pharmacokinetics and anticoagulation of warfarin in rats.

Methods: We studied four Sprague-Dawley rat groups: a negative control group receiving only oral warfarin, a test group receiving warfarin plus piperine, a positive control group receiving warfarin plus sulfaphenazole (CYP2C inhibitor), and another positive control group receiving warfarin plus ketoconazole (CYP3A inhibitor). We also analyzed plasma concentrations of warfarin and its major metabolite, 7-hydoxywarfarin. Blood clotting time, calculated as international normalized ratio (INR), was also measured.

Results: Our results showed that although co-administration of piperine produced a non-significant decrease in warfarin concentrations, it resulted in significantly lower 7-hydroxywarfarin metabolite concentrations. Piperine significantly decreased, by sixfold, AUC_0-∞, by eightfold, C_max, but significantly increased, by fivefold, CL/F and, by sixfold, Vd/F of 7-hydroxywarfarin. The INR values were consistent with the decrease in warfarin concentration in the presence of piperine and showed a significant decrease at 24 h after warfarin dose.

Conclusion: We conclude that piperine could be a potent inhibitor of cytochrome P450 metabolism of warfarin in vivo and, contrary to the expectation, may reduce the plasma concentration and anticoagulation of warfarin. This interaction could have a clinical significance and should be investigated in patients.

Keywords: 7-hydroxywarfarin; black pepper; herb–drug interaction; pharmacokinetics; piperine; warfarin.

Figure 1

The plasma mean concentration versus time profiles of warfarin determined after administration of a single oral dose of warfarin alone (2 mg/kg), warfarin (2 mg/kg) with piperine (20 mg/kg, p.o.), warfarin (2 mg/kg) with sulfaphenazole (120 mg/kg, p.o.), and warfarin (2 mg/kg) with ketoconazole (30 mg/kg, p.o.) in Sprague-Dawley rats. Data are shown in mean ± SEM, n=6.

Figure 2

The plasma mean concentration versus time profiles of 7-hydroxywarfarin determined after administration of a single oral dose of warfarin alone (2 mg/kg), warfarin (2 mg/kg) with piperine (20 mg/kg, p.o.), warfarin (2 mg/kg) with sulfaphenazole (120 mg/kg, p.o.), and warfarin (2 mg/kg) with ketoconazole (30 mg/kg, p.o.) in Sprague-Dawley rats. Data are shown in mean ± SEM, n=6.

Figure 3

Relative formation of 7-hydroxywarfarin to warfarin, calculated as AUC_{7-hydroxywarfarin}/AUC_warfarin, after administration of a single oral dose of warfarin alone (2 mg/kg), warfarin (2 mg/kg) with piperine (20 mg/kg, p.o.), warfarin (2 mg/kg) with sulfaphenazole (120 mg/kg, p.o.), and warfarin (2 mg/kg) with ketoconazole (30 mg/kg, p.o.) in Sprague-Dawley rats. Data are shown in mean ± SEM. *p<0.05, **p<0.01.

Figure 4

Comparison of INR values for warfarin between different rat groups following a single oral dose of warfarin alone (2 mg/kg), warfarin (2 mg/kg) with piperine (20 mg/kg, p.o.), warfarin (2 mg/kg) with sulfaphenazole (120 mg/kg, p.o.), and warfarin (2 mg/kg) with ketoconazole (30 mg/kg, p.o.). Data are shown in mean ± SEM, n=6. *p<0.05.