<p>Piperine Alters the Pharmacokinetics and Anticoagulation of Warfarin in Rats</p>

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 nonsignificant 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.

Case report on interaction of warfarin with herbal medicine “kadha”

“…The interaction of warfarin with herbal products has been suspected in the literature through a variety of case reports. 7 , 8 , 9 In our case report, after a comprehensive literature review, we found that a total of 3–4 herbs were interacting with warfarin (herb-drug interaction) and 2 herbs reacting concomitantly with each other (herb-herb interactions) resulting in improper anticoagulation. They mainly included black pepper, ginger, clove, cinnamon, and cardamom interacting with warfarin followed by estimated herb-herb interaction between cinnamon and dry ginger.…”

“…Aref Zayed et al 7 conducted a study in rats that concluded that piperine, an active compound present in black pepper is a potent inhibitor of cytochrome 450 for warfarin metabolism, thereby reducing the plasma concentration of warfarin. In another case report by Rubin et al 8 in 2019 a 70 year old female prescribed with warfarin 7.5 mg daily except 10 mg on Wednesdays, found an elevated INR of 8.0.…”

Safety Aspects of the Use of Isolated Piperine Ingested as a Bolus

“…By contrast, animal studies were also identified in which no improved drug bioavailability or a decreased bioavailability was observed for the combined administration of piperine with drugs, i.e., with cefadroxil, carbamazepine, warfarin or diltiazem [ 127 , 147 , 148 , 149 ].…”

Anti-inflammatory effect of different curcumin preparations on adjuvant-induced arthritis in rats

“…Curcumin is a lipid-soluble molecule, thus by increasing biliary excretion, it enhances lipid absorption, together with dissolved curcumins. The other mechanism of action is that piperine can inhibit the metabolism of curcumin [ 15 , 17 , 18 ]. There are many studies which show how piperine impacts the concentration of various drugs in serum by inhibiting proteins involved in active metabolism, for example, piperine could be a potent inhibitor of cytochrome P450 which is involved in warfarin – anticoagulant metabolism [ 17 , 19 – 21 ].…”

“…The other mechanism of action is that piperine can inhibit the metabolism of curcumin [ 15 , 17 , 18 ]. There are many studies which show how piperine impacts the concentration of various drugs in serum by inhibiting proteins involved in active metabolism, for example, piperine could be a potent inhibitor of cytochrome P450 which is involved in warfarin – anticoagulant metabolism [ 17 , 19 – 21 ]. Other innovative forms include curcumin nanoemulsion, micellar curcumin, cyclodextrin curcumin, which also increases curcumin bioavailability in both animal and human subjects [ 15 , 22 , 23 ].…”