Document Detail


CYP2C8- and CYP3A-mediated C-demethylation of (3-{[(4-tert-butylbenzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid (CP-533,536), an EP2 receptor-selective prostaglandin E2 agonist: characterization of metabolites by high-resolution liquid chromatography-tandem mass spectrometry and liquid chromatography/mass spectrometry-nuclear magnetic resonance.
MedLine Citation:
PMID:  18653741     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
CP-533,536, (3-{[(4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid (1), an EP2 receptor-selective prostaglandin E2 agonist, is being developed to aid in the healing of bone fractures. To support the development of this program, in vitro metabolism of 1 was investigated in human liver microsomes and major recombinant human cytochrome P450 (P450) isoforms. 1 was metabolized in vitro by at least three recombinant human P450s: CYP3A4, CYP3A5, and CYP2C8. The turnover of 1 was NADPH-dependent and was completely inhibited by ketoconazole and quercetin in the CYP3A4/5 and CYP2C8 incubations, respectively. The major metabolic pathways were caused by oxidation of the tert-butyl moiety to form the omega-hydroxy metabolite (M4), oxidation of the pyridine moiety, and/or N-dealkylation of the methylphenoxy acetic acid moiety. The alcohol metabolite M4 was further oxidized to the corresponding carboxylic acid M3. In addition to these pathways, three unusual metabolites (M22, M23, and M26) resulting from C-demethylation of the tert-butyl group were identified using high-resolution liquid chromatography/tandem mass spectrometry and liquid chromatography/mass spectrometry/NMR. The C-demethylated metabolites were not detected on incubation of carboxylic acid metabolite M3 with either human liver microsomes or CYP3A/2C8 isoforms, suggesting that these metabolites were not derived from decarboxylation of M3. A possible mechanism for C-demethylation may involve the oxidation of M4 to form an aldehyde metabolite (M24), followed by P450-mediated deformylation, to give an unstable carbon-centered radical and formic acid. The carbon-centered radical intermediate then undergoes either oxygen rebound to form an alcohol metabolite M23 or hydrogen abstraction leading to an olefin metabolite M26.
Authors:
Chandra Prakash; Weiwei Wang; Thomas O'Connell; Kim A Johnson
Publication Detail:
Type:  Journal Article     Date:  2008-07-24
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  36     ISSN:  1521-009X     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-09-23     Completed Date:  2008-12-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2093-103     Citation Subset:  IM    
Affiliation:
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton, Connecticut, USA. chandra.prakash@biogenidec.com
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Aged
Aryl Hydrocarbon Hydroxylases / metabolism*
Chromatography, High Pressure Liquid / methods*
Cytochrome P-450 Enzyme System / metabolism*
Dinoprostone / agonists*
Female
Humans
Magnetic Resonance Spectroscopy
Male
Mass Spectrometry
Methylation
Microsomes, Liver / drug effects,  enzymology
Middle Aged
Pyridines / pharmacokinetics*,  pharmacology
Receptors, Prostaglandin E / drug effects*
Chemical
Reg. No./Substance:
0/CP533536; 0/Pyridines; 0/Receptors, Prostaglandin E; 0/prostaglandin EP2 receptor; 363-24-6/Dinoprostone; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP2C8 protein, human; EC 1.14.14.1/CYP3A protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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