The metabolism of DuP 753, a nonpeptide angiotensin II receptor antagonist, by rat, monkey, and human liver slices.
The in vitro metabolism of DuP 753, a novel nonpeptide angiotensin II receptor antagonist, has been investigated in incubations with liver slice preparations from rats, monkeys and humans. Metabolites were identified by HPLC/MS, FAB/MS, Cl/MS, and/or 1H NMR. In the rat, the primary route of metabolism was oxidative, leading to either monohydroxylated or oxidized (carboxylic acid) metabolites, whereas in monkeys, glucuronidation of the tetrazole moiety predominated. An equal mixture of both oxidized and glucuronic acid-conjugated metabolites was isolated from incubations with human liver slices. All metabolites were tested in an in vitro assay to determine their activity as angiotensin II receptor antagonists. The monohydroxylated products and glucuronic acid conjugates were determined to be much less active than DuP 753. Biotransformation to the carboxylic acid, however, was shown to dramatically increase the activity of this agent. The in vivo duration of action of DuP 753 has been observed to be much longer in the rat than in the monkey. This may be explained, at least in part, by these in vitro metabolism studies. The predominance of glucuronidation observed in incubations with monkey liver slices would yield metabolites with diminished activity and might be expected to shorten the in vivo duration of DuP 753 in that species. The oxidative conversion to the carboxylic acid metabolite, along with the low level of glucuronidation observed in incubations with rat liver slices, may be responsible for the prolonged duration observed in vivo in the rat.
Department of Animal and Exploratory Drug Metabolism, Merck Sharp and Dohme Research Laboratories, Rahway, NJ 07065-0900.
R A
RA
Stearns
R R
RR
Miller
G A
GA
Doss
P K
PK
Chakravarty
A
A
Rosegay
G J
GJ
Gatto
S H
SH
Chiu
D000818:Animals; D001711:Biotransformation; D001713:Biphenyl Compounds / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D019808:Losartan; D008253:Macaca mulatta; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013777:Tetrazoles / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology
D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D019808:Losartan