PRODRUGS TO IMPROVE THE ORAL BIOAVAILABILITY OF A DIACIDIC NONPEPTIDEANGIOTENSIN-II ANTAGONIST

DMP 811 is a diacidic angiotensin II antagonist. It has relatively low oral bioavailability in rats. A prodrug approach to improving oral bi oavailability was tested. Five esters were synthesized and their stabi lity in rat plasma in vitro was determined. The hydrolysis rates of th ese five esters ranged from almost immediate to negligible. A simple n -propyl ester was hydrolyzed very slowly (<10% in 24 hr) in rat plasma in vitro, and after oral dosing in rats plasma prodrug concentrations were much greater than DMP 811 concentrations. A pivaloyloxymethyl es ter (1) was hydrolyzed relatively rapidly in rat plasma in vitro. Prod rug 1 was rapidly hydrolyzed by the intestine in vitro, and the intest inal permeation of DMP 811 was increased. DMP 811 oral bioavailability was 47% in rats dosed with 10 mg/kg 1, compared to 11% for rats dosed with 10 mg/kg DMP 811. However, DMP 811 bioavailability was only 27% after a 2 mg/kg dose of 1. In vitro plasma hydrolysis of 1 was highly species-dependent, with a half-life of 13 hr in human plasma but only 1 min in rat plasma. The prodrug approach has potential for improving the oral bioavailability of DMP 811, but selection of the optimal prod rug must be done in humans or in a species, such as dogs, with hydroly sis characteristics closer to humans.