PRODRUGS OF BMS-183920 - METABOLISM AND PERMEABILITY CONSIDERATIONS

The oral bioavailability of BMS-183920, a diacidic, potent angiotensin II receptor antagonist, is low in rats (similar to 11%), in viva stud ies in bile duct-cannulated rats indicated that BMS-183920 was metabol ically stable and that the law bioavailability was due to incomplete i ntestinal absorption. Five acyl-ester prodrugs were synthesized which were 5-15 times more permeable than BMS-183920 through Caco-2 cells. H owever, limited studies in rats indicated that the oral bioavailabilit y of BMS-183920 was improved only 2-fold, in the best case. The lack o f a substantial increase in bioavailability was apparently due to pres ystemic prodrug hydrolysis or metabolism via N-glucuronidation. Bioava ilability of BMS-183920 after oral dosing of a tetrazole-ester prodrug averaged 37%, the most significant improvement within this prodrug se ries, interestingly, in vitro studies indicated that the tetrazole-est er prodrug was a substrate for glucuronosyl transferase; however, its rate of bioactivation (hydrolysis) was sufficiently high to provide a substantial increase in bioavailability of BMS-183920. Therefore, whil e prodrug modification of BMS-183920 improved Caco-2 cell permeability and oral absorption in vivo, the relative extents of hydrolysis (bioa ctivation) vs metabolism of the prodrug determined whether a substanti al improvement in bioavailability was achieved.