Intestinal Absorption Mechanism of Casearin X

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 at low concentrations. In this work, the intestinal absorption mechanism of 1 was evaluated using Caco-2 cells with and without active carboxylesterases (CES) hydrolysis. The estimation of permeability coefficients was only possible under CES-inhibited conditions, in which 1 is able to cross the Caco-2 cells monolayer. The mechanism is probably by active transport, with no significant efflux, but with a high retention of the compound inside the cells.

Since 1 demonstrates to be a substrate for human carboxyesterases, we can expect that the extent of hydrolysis can significantly lower its bioavailability due to intestinal first-pass metabolism.

This can provide important information to guide chemical modifications and potential alterations in hydrolytic susceptibility of 1.