Rhinacanthin-C mediated herb-drug interactions with drugtransporters and phase i drug-metabolizing enzymes

Abstract

Rhinacanthin-C is a major active constituent in Rhinacanthus nasutus (L.) Kurz, a plant widely used in herbal remedies. Its potential for pharmacokinetic herb-drug interaction may exist with drug transporters and drug metabolizing enzymes. This study assessed the possibility for rhinacanthin-C-mediated drug interaction by determining its inhibitory effects against major human efflux and influx drug transporters as well as various human cytochrome P450(CYP) isoforms. Rhinacanthin-C demonstrated a moderate permeability through the Caco-2 monolayers [Papp (AP-to-BL) 5 1.26 3 1026 cm/s]. It significantly inhibited transport mediated by both P-glycoprotein (P-gp) (IC50 5 5.20 mM) and breast cancer resistance protein (BCRP) (IC50 5 0.83 mM) across Caco-2 and BCRPoverexpressing Madin-Darby canine kidney II cells (MDCKII) cells. This compound also strongly inhibited uptake mediated by organic anion-transporting polypeptide 1B1 (OATP1B1) (IC50 5 0.70 mM) and OATP1B3 (IC50 5 3.95 mM) in OATP1B-overexpressing HEK cells. In addition to its inhibitory effect on these drug transporters, rhinacanthin-C significantly inhibited multiple human CYP isoforms including CYP2C8 (IC50 5 4.56 mM), 2C9 (IC50 5 1.52 mM), 2C19 (IC50 5 28.40 mM), and 3A4/5 (IC50 5 53 mM for midazolam and IC50 5 81.20 mM for testosterone), but not CYP1A2, 2A6, 2B6, 2D6, and 2E1. These results strongly support a high propensity for rhinacanthin-C as a perpetrator of clinical herb-drug interaction via inhibiting various influx and efflux drug transporters (i.e., P-gp, BCRP, OATP1B1, and OATP1B3) and CYP isoforms (i.e., CYP2C8, CYP2C9, and CYP2C19). Thus, the potential for significant pharmacokinetic herb-drug interaction should be addressed when herbal products containing rhinacanthin-C are to be used in conjunction with other prescription drugs.