Evaluation of the intestinal absorption mechanism of casearin X in Caco-2 cells with Modified carboxylesterase activity

Abstract

The clerodane diterpene casearin X (1)​, isolated from the leaves of Casearia sylvestris, is a potential new drug candidate due to its potent in vitro cytotoxic activity. In this work, the intestinal absorption mechanism of 1 was evaluated using Caco-​2 cells with and without active carboxylesterases (CES)​. An LC-​MS method was developed and validated for the quantification of 1. The estn. of permeability coeffs. was possible only under CES-​inhibited conditions in which 1 is able to cross the Caco-​2 cell monolayer. The mechanism is probably by active transport, with no significant efflux, but with a high retention of the compd. inside the cells. The enzymic hydrolysis assay demonstrates the susceptibility of 1 to first-​pass metab. as substrate for specific CES expressed in human intestine.