The in vitro hepatic metabolism of ABT-418, a cholinergic channel activator, in rats, dogs, cynomolgus monkeys, and humans.
The metabolism of the cholinergic channel activator [3H]ABT-418 was studied in 9,000g supernatant (S-9) fractions and precision-cut tissue slices prepared from rat, dog, monkey, and human livers. In rat S-9 fractions and tissue slices, the lactam and trans N'-oxide were detected as major metabolites. The lactam was also the major metabolite in monkey and human S-9 fractions and tissue slices, although the rate of formation was greater in monkey (Vmax' of 428 vs. 103 pmol/min/mg S-9 protein). Trans N'-oxide was not detected in either species, but low levels of the cis N'-oxide were detected in tissue slice preparations from two human subjects. In contrast, trans ABT-418 N'-oxide was identified as a major metabolite in dog S-9 fractions (Vmax' of 266 pmol metabolite formed/min/mg S-9 protein) and tissue slices. Although identified as a minor metabolite in dog S-9 fractions, the lactam metabolite was shown to account for a sizeable proportion of the total radioactivity in the corresponding tissue slice preparations (22% of the total radioactivity at 12 hr); the rank order of lactam formation by the precision-cut liver slices was monkey > human > rat > or = dog. Evidence that N'-oxidation and C-oxidation (to lactam) of ABT-418 was mediated by liver microsomal flavin-containing mono-oxygenase (FMO) and cytochromes P-450 (CYPs), respectively, was obtained with the inhibitors thiobenzamide and clotrimazole. The involvement of cytosolic aldehyde oxidase (AO) was suggested by a significant correlation (r2 = 0.998, p < 0.01) between the observed rate of lactam formation and AO (N1-methylnicotinamide oxidase) activity in rat, dog, monkey, and human S-9 fractions; inhibition of lactam formation by the AO substrate N1-methylnicotinamide; and the lack of lactam formation in the absence of cytosol. Data indicate that the species-related differences in the hepatic metabolism of ABT-418 may be dependent on the relative levels and/or activity of FMO, CYP, and AO. In this regard, ABT-418 is very similar to nicotine. However, unlike nicotine, the N-demethylation of parent drug and the further products of lactam metabolism was not detected.
Rodrigues
A D
AD
Department of Drug Metabolism, Abbott Laboratories, Abbott Park, IL 60064-3500.
Ferrero
J L
JL
Amann
M T
MT
Rotert
G A
GA
Cepa
S P
SP
Surber
B W
BW
Machinist
J M
JM
Tich
N R
NR
Sullivan
J P
JP
Garvey
D S
DS
D000328:Adult; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D007555:Isoxazoles / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D011759:Pyrrolidines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
D014151:Anti-Anxiety Agents; D007473:Ion Channels; D007555:Isoxazoles; D011759:Pyrrolidines; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; D009249:NADP; D006899:Mixed Function Oxygenases