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-H-3]ABT-418 was studied using precision-cut tissue slices and microsomes (+/-cytos ol) prepared from a single chimpanzee liver. In both cases, the produc ts of C-oxidation (lactam) and N'-oxidation lets a trans) were detecte d, In the presence of chimpanzee liver microsomes and cytosol, which h ad been characterized with respect to the levels of aldehyde oxidase ( N-1-methylnicotinamide oxidase), NADPH-dependent flavin-containing mon ooxygenase (FMO; N, N-dimethylaniline N-oxidase), and various cytochro me P450 (CYP)-dependent monooxygenase activities, ABT-418 lactam and N '-oxide formation was found to be largely dependent on CYP/aldehyde ox idase and FMO, respectively, The rank order of total (trans + cis) FMO -dependent N'-oxidation in liver microsomes was dog > rat > rabbit > c himpanzee greater than or equal to cynomolgus monkey a human, It is co ncluded that the metabolic profile of ABT-418 in the chimpanzee is uni que, First, the C-/N'-oxidation ratio in liver slices (0,43) is simila r to that of the rat and dog and dissimilar to that of the two other p rimate species studied; human and cynomolgus monkey (C-/N'-oxidation r atio greater than or equal to 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 mic rosomes, rat and human kidney S-9 (trans much greater than cis), human liver microsomes (trans:cis similar to 1:1), and cynomolgus monkey (t rans:cis similar to 2:1) liver microsomes, Lack of stereoselective N'- oxidation by human FMO was confirmed with cDNA-expressed FMO(3).