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.
نویسندگان
چکیده
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.
منابع مشابه
Metabolism, excretion, and pharmacokinetics of (3-{[4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid, an EP2 receptor-selective prostaglandin E2 agonist, in male and female Sprague-Dawley rats.
Metabolism, excretion, and pharmacokinetics of a highly selective EP2 agonist, CP-533,536 (3-{[4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid), were investigated in male and female Sprague-Dawley rats following an intravenous administration of a single 15 mg/kg dose of [(14)C]CP-533,536. At 144 h after the dose, the cumulative excretion of radioactivity averaged ...
متن کاملMetabolism, Excretion and Pharmacokinetics of (3-{[4-tert- Butyl-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)- Acetic Acid, an Ep-2 Receptor Selective Pge2 Agonist, in Male and Female Sprague-dawley Rats Kim a Johnson and Chandra Prakash
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عنوان ژورنال:
- Drug metabolism and disposition: the biological fate of chemicals
دوره 36 10 شماره
صفحات -
تاریخ انتشار 2008