Permeability of a novel beta-lactamase inhibitor LK-157 and its ester prodrugs across rat jejunum in vitro.

LK-157 is a novel 10-ethylidene tricyclic carbapenem that resembles the structure of the broad-spectrum antibiotic sanfetrinem and acts as a potent inactivator of beta-lactamases of classes A, C and D. LK-157 is a highly soluble but poorly permeable drug. Since most of the beta-lactams are poorly absorbed, ester prodrugs LK-159, LK-157E1 and LK-157E2 were designed to enhance membrane permeability. This study investigated the permeability of LK-157 and the three ester prodrugs across rat intestine in vitro. The morpholinoethyl ester of sanfetrinem was also investigated. Permeability across rat jejunum was determined using EasyMount side-by-side diffusion chambers. The solubility and permeability of morpholinoethyl ester LK-157E2 were superior to those of LK-159 and LK-157E1. The morpholinoethyl ester of sanfetrinem LK-176E1 had the highest observed permeability coefficient and consequently the highest predicted absorption in humans. These results suggest that the morpholinoethyl esters of LK-157 and sanfetrinem could be further investigated to assess bioavailability in vivo.