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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

Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton, Connecticut

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 (AUC_0-)] 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 -hydroxy metabolite M4 (males, 19.7%; females, 6.5%). M4 was further oxidized to form the -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. -Carboxy metabolite M3 was the major metabolite in male rats, whereas M3-sulfate was identified as the major metabolite in female rats.

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