Potential P-glycoprotein-mediated herb-drug interaction of phyllanthin at the intestinal absorptive barrier.

Abstract

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. 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. 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. 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.