RT Journal Article
SR Electronic
T1 The in vitro hepatic metabolism of ABT-418, a cholinergic channel activator, in rats, dogs, cynomolgus monkeys, and humans.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 788
OP 798
VO 22
IS 5
A1 A D Rodrigues
A1 J L Ferrero
A1 M T Amann
A1 G A Rotert
A1 S P Cepa
A1 B W Surber
A1 J M Machinist
A1 N R Tich
A1 J P Sullivan
A1 D S Garvey
YR 1994
UL http://dmd.aspetjournals.org/content/22/5/788.abstract
AB 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.