title: Prodrugs of BMS-183920: metabolism and permeability considerations.
abstract: The oral bioavailability of BMS-183920, a diacidic, potent angiotensin II receptor antagonist, is low in rats (approximately 11%). In vivo studies in bile duct-cannulated rats indicated that BMS-183920 was metabolically stable and that the low bioavailability was due to incomplete intestinal absorption. Five acyl-ester prodrugs were synthesized which were 5-15 times more permeable than BMS-183920 through Caco-2 cells. However, limited studies in rats indicated that the oral bioavailability of BMS-183920 was improved only 2-fold, in the best case. The lack of a substantial increase in bioavailability was apparently due to presystemic prodrug hydrolysis or metabolism via N-glucuronidation. Bioavailability of BMS-183920 after oral dosing of a tetrazole-ester prodrug averaged 37%, the most significant improvement within this prodrug series. Interestingly, in vitro studies indicated that the tetrazole-ester 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, while prodrug modification of BMS-183920 improved Caco-2 cell permeability and oral absorption in vivo, the relative extents of hydrolysis (bioactivation) vs metabolism of the prodrug determined whether a substantial improvement in bioavailability was achieved.
authors.affiliation: Metabolism and Pharmacokinetics Department, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Obermeier
authors.forename: S
authors.initials: S
authors.lastname: Chong
authors.forename: S A
authors.initials: SA
authors.lastname: Dando
authors.forename: A M
authors.initials: AM
authors.lastname: Marino
authors.forename: D E
authors.initials: DE
authors.lastname: Ryono
authors.forename: A
authors.initials: A
authors.lastname: Starrett-Arroyo
authors.forename: G C
authors.initials: GC
authors.lastname: DiDonato
authors.forename: B M
authors.initials: BM
authors.lastname: Warrack
authors.forename: R E
authors.initials: RE
authors.lastname: White
authors.forename: R A
authors.initials: RA
authors.lastname: Morrison
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics*; D011804:Quinolines / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D011355:Prodrugs; D011804:Quinolines; D013777:Tetrazoles; C103295:BMS 183920