RT Journal Article
SR Electronic
T1 Evidence for a 1,2-hydride shift in the microsomal metabolism of the heterocycle L-158,338, a nonpeptide angiotensin II receptor antagonist.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 670
OP 676
VO 21
IS 4
A1 R A Stearns
A1 R R Miller
A1 B H Arison
A1 A Rosegay
A1 J L Smith
A1 N B Mantlo
A1 S H Chiu
YR 1993
UL http://dmd.aspetjournals.org/content/21/4/670.abstract
AB L-158,338 is an imidazo[4,5-b]pyridine derivative that is a potent and highly selective angiotensin II receptor antagonist. Rat liver microsomal metabolism of [C6-3H]L-158,338 gave a major metabolite that was monohydroxylated at the C6 position of the imidazo-pyridine but showed partial retention of the radiolabel. This biotransformation necessitated a shift of the radiolabel from the C6 position to another site within the molecule. We have investigated the mechanism of this biotransformation using 3H-, 3H/14C-, and 2H-labeled L-158,338. Metabolites were identified by FAB/MS, LC/MS, and 1H-NMR. Results of these studies show that the microsomal metabolism of L-158,338 to its C6-monohydroxylated derivative was mediated by a 1,2 hydride shift.