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 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-infinity))] 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 omega-hydroxy metabolite M4 (males, 19.7%; females, 6.5%). M4 was further oxidized to form the omega-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. omega-Carboxy metabolite M3 was the major metabolite in male rats, whereas M3-sulfate was identified as the major metabolite in female rats.
Johnson
Kim A
KA
Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton, CT 06340, USA.
Prakash
Chandra
C
D000818:Animals; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D015232:Dinoprostone / Q000819:agonists*; D005243:Feces / Q000737:chemistry; D005260:Female; D008297:Male; D013058:Mass Spectrometry; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D012737:Sex Factors
C475539:CP533536; D002250:Carbon Radioisotopes; D011725:Pyridines; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D015232:Dinoprostone