Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4

Abstract

Dietary constituents (e.g., in grapefruit juice; NaCl) and phytochemicals (e.g., St. John's wort) are important agents modifying drug metabolism and transport and thereby contribute to interindividual variability in drug disposition. Most of these drug-food interactions are due to induction or inhibition of P-glycoprotein and/or CYP3A4. Preliminary data indicate that piperine, a major component of black pepper, inhibits drugmetabolizing enzymes in rodents and increases plasma concentrations of several drugs, including P-glycoprotein substrates (phenytoin and rifampin) in humans. However, there are no direct data whether piperine is an inhibitor of human Pglycoprotein and/or CYP3A4. We therefore investigated the influence of piperine on P-glycoprotein-mediated, polarized transport of digoxin and cyclosporine in monolayers of Caco-2 cells. Moreover, by using human liver microsomes we determined the effect of piperine on CYP3A4-mediated formation of the verapamil metabolites D-617 and norverapamil. Piperine inhibited digoxin and cyclosporine A transport in Caco-2 cells with IC 50 values of 15.5 and 74.1 M, respectively. CYP3A4-catalyzed formation of D-617 and norverapamil was inhibited in a mixed fashion, with K i values of 36 Ϯ 8 (liver 1)/49 Ϯ 6 (liver 2) and 44 Ϯ 10 (liver 1)/77 Ϯ 10 M (liver 2), respectively. In summary, we showed that piperine inhibits both the drug transporter P-glycoprotein and the major drug-metabolizing enzyme CYP3A4. Because both proteins are expressed in enterocytes and hepatocytes and contribute to a major extent to first-pass elimination of many drugs, our data indicate that dietary piperine could affect plasma concentrations of P-glycoprotein and CYP3A4 substrates in humans, in particular if these drugs are administered orally.Several dietary constituents and phytochemicals are now identified as important factors affecting drug disposition

Concise Review: Clinical Relevance of Drug–Drug and Herb–Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein)

“…Indeed, piperine [53], ginsenosides [54,55], silymarin from milk thistle and other flavonoids [56], capsaicin [57], and resveratrol [57] were reported to inhibit P-gp activity in vitro, whereas curcumin [58,59] and curcuminoids [60] and several catechins from green tea [61][62][63] were shown to reduce P-gp expression and activity in vitro. Importantly, some of these herbal constituents (such as piperine, silymarin) have been observed to interact with P-gp at dietary concentrations, thus making a drug-herbal interaction in vivo more likely [53,56]. Similarly, constituents of grapefruit and orange juice were also found to block P-gp function and certain juice-drug interactions for commonly used drugs have been described too [64 -70].…”

The dark side of curcumin

“…14 This strategy, however, should be used cautiously, as piperine is a potent inhibitor of drug metabolism and may cause toxicity in people taking specific drugs. 8,19,20 In addition, it is important to note that any strategy that increases the levels of curcumin in tissues will not only increase the effectiveness of curcumin, but also its toxicity.…”

Piperine and Its Various Physicochemical and Biological Aspects: A Review

“…Literature concludes that piperine was used as effective bioavailability enhancer, inhibits the human P-glycoprotein and CYP3A4 a class of enzyme belonging to cytochrome P450 family [78] and enable the particular molecule to remain in biological system for much longer period. In various experimental studies, it has been shown that piperine when compounded with different molecules (drugs) enhances the bioavalibilty of β-lactumantibiotics [79,80], amoxicillin trihydrate and cefotaxime sodium [81], paeoniflorin [82], rifampicin [83,84], phenytoin [85], oxyphenolbutazone [86], nimesulide [87] and NSAIDS [88] or derivatives significantly.…”

“…Piperine, tetrahydropiperine, its analogs and derivatives also act as bioavailability enhancer of various nutrients including vitamins, β -carotene and selenium [78] and pharmaceuticals [91]. Various in vitro and in vivo studies concludes that the biotransformation of both water soluble and lipid soluble xenbiotics catalysed by pulmonary cytochrome P450 was likely to be affected or inhibited by presence of piperine [92].…”