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In vitro metabolism studies of nomifensine monooxygenation pathways: metabolite identification, reaction phenotyping, and bioactivation mechanism.
Drug Metab Dispos. 2010 Oct; 38(10):1767-78.DM

Abstract

Multiple GSH adducts of the oxidative products of nomifensine (M1-M9) in human hepatocytes and liver microsomes have been identified recently. The current study reports three new types of monooxygenated metabolites of nomifensine identified in human liver microsomes: C-linked hydroxylated metabolites with modifications at the A ring (H1 and H4), an N-hydroxylamine (H6), and nomifensine N-oxides (H7 and H8). GSH conjugate formation in incubates containing cDNA-expressed P450s and GSH suggests that nomifensine GSH-sulfinamides (M1 and M2) are formed through the reaction between GSH and the oxidative product of H6. C-linked GSH conjugates M3, M4, M5, and M6 are probably formed via nomifensine benzoquinone imine intermediates via H4 and/or nomifensine epoxides. C-linked GSH conjugates M7, M8, and M9 are probably formed through similar mechanisms via H1. Nomifensine N-oxides do not form reactive metabolites that react with GSH. In vitro metabolism studies using a panel of cDNA-expressed human P450 and flavin monooxygenase (FMO) isoforms (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, FMO1, FMO3, and FMO5) indicated that CYP3A4, CYP2C19, and CYP2B6 generate the largest quantities of H1, H4, and H6, respectively. H7 and H8 are formed almost exclusively by FMOs. The contribution of the individual P450s involved in the formation of H1, H4, and H6 in human liver microsomes was confirmed by the inhibition of product formation by monoclonal anti-cytochrome 450 antibodies. These results showed that CYP3A4 and CYP2B6 contributed primarily to the formation of H1 and H6, respectively. CYP2C19 and CYP1A2 seemed to contribute significantly to the formation of H4.

Authors+Show Affiliations

Departments of Discovery Drug Metabolism and Pharmacokinetics,AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, Wilmington, DE 19850-5437, USA. jian.yu@astrazeneca.comNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20595377

Citation

Yu, Jian, et al. "In Vitro Metabolism Studies of Nomifensine Monooxygenation Pathways: Metabolite Identification, Reaction Phenotyping, and Bioactivation Mechanism." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 38, no. 10, 2010, pp. 1767-78.
Yu J, Brown DG, Burdette D. In vitro metabolism studies of nomifensine monooxygenation pathways: metabolite identification, reaction phenotyping, and bioactivation mechanism. Drug Metab Dispos. 2010;38(10):1767-78.
Yu, J., Brown, D. G., & Burdette, D. (2010). In vitro metabolism studies of nomifensine monooxygenation pathways: metabolite identification, reaction phenotyping, and bioactivation mechanism. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 38(10), 1767-78. https://doi.org/10.1124/dmd.110.033910
Yu J, Brown DG, Burdette D. In Vitro Metabolism Studies of Nomifensine Monooxygenation Pathways: Metabolite Identification, Reaction Phenotyping, and Bioactivation Mechanism. Drug Metab Dispos. 2010;38(10):1767-78. PubMed PMID: 20595377.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro metabolism studies of nomifensine monooxygenation pathways: metabolite identification, reaction phenotyping, and bioactivation mechanism. AU - Yu,Jian, AU - Brown,Dean G, AU - Burdette,Doug, Y1 - 2010/07/01/ PY - 2010/7/3/entrez PY - 2010/7/3/pubmed PY - 2011/2/16/medline SP - 1767 EP - 78 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 38 IS - 10 N2 - Multiple GSH adducts of the oxidative products of nomifensine (M1-M9) in human hepatocytes and liver microsomes have been identified recently. The current study reports three new types of monooxygenated metabolites of nomifensine identified in human liver microsomes: C-linked hydroxylated metabolites with modifications at the A ring (H1 and H4), an N-hydroxylamine (H6), and nomifensine N-oxides (H7 and H8). GSH conjugate formation in incubates containing cDNA-expressed P450s and GSH suggests that nomifensine GSH-sulfinamides (M1 and M2) are formed through the reaction between GSH and the oxidative product of H6. C-linked GSH conjugates M3, M4, M5, and M6 are probably formed via nomifensine benzoquinone imine intermediates via H4 and/or nomifensine epoxides. C-linked GSH conjugates M7, M8, and M9 are probably formed through similar mechanisms via H1. Nomifensine N-oxides do not form reactive metabolites that react with GSH. In vitro metabolism studies using a panel of cDNA-expressed human P450 and flavin monooxygenase (FMO) isoforms (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, FMO1, FMO3, and FMO5) indicated that CYP3A4, CYP2C19, and CYP2B6 generate the largest quantities of H1, H4, and H6, respectively. H7 and H8 are formed almost exclusively by FMOs. The contribution of the individual P450s involved in the formation of H1, H4, and H6 in human liver microsomes was confirmed by the inhibition of product formation by monoclonal anti-cytochrome 450 antibodies. These results showed that CYP3A4 and CYP2B6 contributed primarily to the formation of H1 and H6, respectively. CYP2C19 and CYP1A2 seemed to contribute significantly to the formation of H4. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/20595377/In_vitro_metabolism_studies_of_nomifensine_monooxygenation_pathways:_metabolite_identification_reaction_phenotyping_and_bioactivation_mechanism_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=20595377 DB - PRIME DP - Unbound Medicine ER -