Abstract
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 [14C]CP-533,536. At 144 h after the dose, the cumulative excretion of radioactivity averaged 98.2 ± 3.44% and 97.0 ± 4.82% in male and female rats, respectively. The radioactivity was predominantly excreted in feces, reaching 87% of the dose. Mean exposure [area under the concentration-time curve (AUC0-∞)] for both CP-533,536 and total radioactivity was higher in female rats than in male rats, whereas the plasma clearance of CP-533,536 and metabolites was lower in female rats compared to male rats. CP-533,536 was extensively metabolized in both male and female rats. The major oxidative pathway was due to the oxidation of the tert-butyl side chain to form the ω-hydroxy metabolite M4 (males, 19.7%; females, 6.5%). M4 was further oxidized to form the ω-carboxy metabolite M3 (males, 32.8%; females 1.66%) or conjugated via sulfation to form metabolite M6 (males 12.7%; females 36.2%). Other metabolites were due to N-oxidation of the pyridine ring (M5) and aromatic hydroxylation (M12), and conjugation with glucuronic acid. The secondary metabolites were due to N-dealkylation of the methyl-phenoxyacetic acid moiety and phase II conjugation. CP-536,536 accounted for about 63 and 72% of the AUC of the total radioactivity for male and female rats, respectively. Gender-related differences in the metabolism and pharmacokinetics were observed. ω-Carboxy metabolite M3 was the major metabolite in male rats, whereas M3-sulfate was identified as the major metabolite in female rats.
Footnotes
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This work was presented in part at the 11th North American ISSX Meeting, Orlando, Florida, Oct. 27–31, 2002.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.004713.
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ABBREVIATIONS: PGE2, prostaglandin E2; SD, Sprague-Dawley; LC/MS/MS, liquid chromatography-tandem mass spectrometry; HPLC, high performance liquid chromatography; radio-HPLC, HPLC with on-line radioactivity detection; RAM, radioactivity monitor; t1/2, terminal phase half-life; AUC0-∞, area under the plasma concentration-time curve from time 0 to infinity; CLp, systemic plasma clearance; VDss, steady-state volume of distribution; CID, collision-induced dissociation; MS, mass spectrometry; CP-533,536, 3-{[4-tert-butyl-benzyl)-(pyridine-3-sulfonyl)-amino]-methyl}-phenoxy)-acetic acid; CP-459,310, 3-{[(4-butyl-benzyl)-methanesulfonyl-amino]-methyl}-phenyl)-acetic acid; IS, internal standard; amu, atomic mass unit(s); LC/MS, liquid chromatography/mass spectrometry.
- Received March 14, 2005.
- Accepted May 9, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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