The efficiency and mechanism of a new absorption enhancer, malic acid, for enhancing the oral bioavailability of docetaxel

Abstract

This study investigated the efficiency and the related mechanisms of a new absorption enhancer, DL-malic acid (MA), on the oral bioavailability of docetaxel (DTX). Polyethylene glycol polycarbonate (PEG-PCL) modified liposomes (PLip) were prepared for DTX, and incorporated into the pH-sensitive microspheres (MS) with sustained release. MA decreased the transepithelial electrical resistance (TEER) across a Caco-2 cell monolayer by 20% and 57% after 2 and 3 h of co-incubation with DTX-PLip and the cells, respectively, indicating that MA could open tight junctions but not instantaneously. After long enough exposure (4 h) of MA to the small intestine of rats, only the absorption rate constant (ka ) of DTX-PLip, but not Duopafei®, was increased, which could be related to the intestinal mucosal permeability of DTX. After co-administration in rats, MA significantly enhanced the oral bioavailability of DTX in DTX-PLip-MS from 44.67% to 81.27%, rather than DTX-PLip and Duopafei®, which could be related to the prolonged intestinal retention time of DTX-PLip via the MS and the promoted drug intercellular transport by MA. The absorption-enhancing effects of MA on DTX-PLip-MS were further confirmed by in vivo imaging. The above findings suggest that MA served as a new and efficient absorption enhancer for DTX-PLip-MS. HIGHlIGHTS In this study, malic acid as a new absorption enhancer for DTX in polymer-liposome (PLip) embedded in pH-sensitive microspheres (MS) was found for the first time. The malic acid could significantly enhance oral bioavailability of DTX in DTX-PLip-MS (from 44.67 % to 81.27%) rather than Duopafei® and DTX-PLip after co-administration. The absorption enhancement may be closely related to the intestinal retention time and mucosal permeability. These findings will provide an important reference for the study of absorption enhancers for promoting intercellular insoluble drug transport.