TY - JOUR T1 - Rhinacanthin-C mediated herb-drug interactions with drug transporters and Phase I drug metabolizing enzymes. JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.118.085647 SP - dmd.118.085647 AU - Wilasinee Dunkoksung AU - Nontima Vardhanabhuti AU - Pongpun Siripong AU - Suree Jianmongkol Y1 - 2019/01/01 UR - http://dmd.aspetjournals.org/content/early/2019/08/09/dmd.118.085647.abstract N2 - 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 CYP450 isoforms. Rhinacanthin-C demonstrated a moderate permeability through the Caco-2 monolayers (Papp (AP-to-BL) = 1.26 × 10-6 cm/s). It significantly inhibited both P-gp (IC50 = 5.20 μM) and BCRP (IC50 = 0.83 μM) mediated transport across Caco-2 and BCRP-overexpressing MDCKII cells. This compound also strongly inhibited OATP1B1 (IC50 = 0.70 μM) and OATP1B3 (IC50 = 3.95 μM) mediated uptake in OATP1B-overexpressing HEK cells. In addition to its inhibitory effect on these drug transporters, rhinacanthin-C significantly inhibited multiple human CYP450 isoforms including CYP2C8 (IC50 = 4.56 μM), 2C9 (IC50 = 1.52 μM), 2C19 (IC50 = 28.40 μM), and 3A4/5 (IC50 = 53 μM for midazolam and IC50 = 81.20 μM for testosterone), but not CYP1A2, 2A6, 2B6, 2D6, and 2E1. These results strongly supported 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 CYP450 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.SIGNIFICANCE STATEMENT Rhinacanthin-C can be a perpetrator of clinical herb-drug interaction via inhibiting various influx and efflux drug transporters (i.e., P-gp, BCRP, OATP1B1 and OATP1B3) and CYP450 isoforms (i.e., CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5). 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. ER -