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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 [P app (AP-to-BL) = 1.26 × 10 -6 cm/s]. It significantly inhibited transport mediated by both P-glycoprotein (P-gp) (IC 50 = 5.20 µ M) and breast cancer resistance protein (BCRP) (IC 50 = 0.83 µ M) across Caco-2 and BCRP-overexpressing Madin-Darby canine kidney II cells (MDCKII) cells. This compound also strongly inhibited uptake mediated by organic anion-transporting polypeptide 1B1 (OATP1B1) (IC 50 = 0.70 µ M) and OATP1B3 (IC 50 = 3.95 µ M) 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 (IC 50 = 4.56 µ M), 2C9 (IC 50 = 1.52 µ M), 2C19 (IC 50 = 28.40 µ M), and 3A4/5 (IC 50 = 53 µ M for midazolam and IC 50 = 81.20 µ M 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.

Rhinacanthin-C Mediated Herb-Drug Interactions with Drug Transporters and Phase I Drug-Metabolizing Enzymes