In vitro hepatic metabolism of ABT-418 in chimpanzee (Pan troglodytes). A unique pattern of microsomal flavin-containing monooxygenase-dependent stereoselective N'-oxidation.
Metabolism of the cholinergic channel activator [N-methyl-3H]ABT-418 was studied using precision-cut tissue slices and microsomes (+/- cytosol) prepared from a single chimpanzee liver. In both cases, the products of C-oxidation (lactam) and N'-oxidation (cis > trans) were detected. In the presence of chimpanzee liver microsomes and cytosol, which had been characterized with respect to the levels of aldehyde oxidase (N1-methylnicotinamide oxidase), NADPH-dependent flavin-containing monooxygenase (FMO; N, N-dimethylaniline N-oxidase), and various cytochrome P450 (CYP)-dependent monooxygenase activities, ABT-418 lactam and N'-oxide formation was found to be largely dependent on CYP/aldehyde oxidase and FMO, respectively. The rank order of total (trans + cis) FMO-dependent N'-oxidation in liver microsomes was dog > rat > rabbit > chimpanzee > or = cynomolgus monkey > human. It is concluded that the metabolic profile of ABT-418 in the chimpanzee is unique. First, the C-/N'-oxidation ratio in liver slices (0.43) is similar to that of the rat and dog and dissimilar to that of the rat and dog and dissimilar to that of the two other primate species studied; human and cynomolgus monkey (C-/N'-oxidation ratio > or = 9.4). Second, the pattern of ABT-418 N'-oxidation observed with chimpanzee liver microsomes, and liver slices (trans:cis = 1:3), differs from that of rat, rabbit, and dog liver microsomes, rat and human kidney S-9 (trans >> cis), human liver microsomes (trans:cis approximately 1:1), and cynomolgus monkey (trans:cis approximately 2:1) liver microsomes. Lack of stereoselective N'-oxidation by human FMO was confirmed with cDNA-expressed FMO3.
Rodrigues
A D
AD
Drug Metabolism Department, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Kukulka
M J
MJ
Ferrero
J L
JL
Cashman
J R
JR
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000502:physiology*; D002679:Pan troglodytes; D011759:Pyrrolidines / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013237:Stereoisomerism
D014151:Anti-Anxiety Agents; D007555:Isoxazoles; D011759:Pyrrolidines; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)