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) 5 1.26 3 10 26 cm/s]. It significantly inhibited transport mediated by both P-glycoprotein (P-gp) (IC 50 5 5.20 mM) and breast cancer resistance protein (BCRP) (IC 50 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) (IC 50 5 0.70 mM) and OATP1B3 (IC 50 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 (IC 50 5 4.56 mM), 2C9 (IC 50 5 1.52 mM), 2C19 (IC 50 5 28.40 mM), and 3A4/5 (IC 50 5 53 mM for midazolam and IC 50 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.

Objectives This study investigated the absorptive potential of phyllanthin across the polarized Caco‐2 monolayers and the potential role of phyllanthin in P‐glycoprotein (P‐gp)‐mediated drug interaction. Methods The absorptive potential of phyllanthin was predicted from its apparent permeability (Papp) across the Caco‐2 monolayers under the pH gradient condition (pH 6.5AP–7.4BL) at 37°C. Integrity of paracellular transport was assessed by monitoring transepithelial electrical resistance (TEER) and lucifer yellow (LY) leakage. P‐gp‐mediated interaction was evaluated by transport studies of phyllanthin and rhodamine‐123. Key findings The absorptive Papp of phyllanthin (34.90 ± 1.18 × 10−6 cm/s) was in the same rank order as the high permeable theophylline and antipyrine. Phyllanthin transport in the absorptive and secretive directions was comparable (the efflux ratio (ER) of 1.19 ± 0.01). Phyllanthin caused no changes in TEER nor LY leakage in the monolayers. However, phyllanthin increased rhodamine‐123 ER in a concentration‐dependent manner, suggesting its inhibition on P‐gp function. In addition, phyllanthin aqueous solubility was <5 μg/ml at 37°C. Conclusions Phyllanthin is a highly permeable compound that could passively diffuse through the absorptive barrier via transcellular pathway with little hindrance from P‐gp. Phyllanthin could interfere with transport of P‐gp drug substrates, when concomitantly administered. In addition, aqueous solubility could be a limiting factor in phyllanthin absorption.