title: In vitro metabolism of nefiracetam by liver microsomes from rats, dogs and monkeys.
abstract: The in vitro metabolism of nefiracetam (CAS 77191-36-7, N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, NEF, DM-9384), a novel cognition enhancer, has been investigated using liver microsomes from rats, dogs and monkeys. Microsomal metabolism of NEF showed qualitatively a similar profile in three species tested. Six metabolites were generated from incubation of NEF with liver microsomes. Their structures were identified using a thermospray LC/MS/MS (liquid chromatography/tandem mass spectrometry) method, as regioisomers of monhydroxylated derivatives of NEF: the 3-hydroxy (3-OH-NEF); 4-hydroxy (4-OH-NEF); 5-hydroxy (5-OH-NEF); 3'-hydroxy (3'-OH-NEF); 4'-hydroxy (4'-OH-NEF); hydroxymethyl (HM-NEF) metabolites. The heat lability, NADPH requirement and inhibition by prototype cytochrome P450 inhibitors (proadifen and metyrapone) implies that NEF oxidations are catalyzed by cytochromes P450. The major metabolic route was 5-OH-NEF formation in all species, corresponding well with the previous investigations in vivo. Inhibitory effects of alpha-naphthoflavone and quinidine on NEF hydroxylation suggest that several isoforms of cytochromes P450 are involved in the formation of these NEF metabolites.
authors.affiliation: Drug Metabolism and Analytical Chemistry Research Center, Daiichi Pharmaceutical Co., Ltd, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Fujimaki
authors.forename: K
authors.initials: K
authors.lastname: Sudo
authors.forename: H
authors.initials: H
authors.lastname: Hakusui
mesh_terms: D000818:Animals; D001711:Biotransformation; D002491:Central Nervous System Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D011760:Pyrrolidinones / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D002491:Central Nervous System Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D011760:Pyrrolidinones; C058876:nefiracetam; D009249:NADP; D003577:Cytochrome P-450 Enzyme System