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Metabolism and Disposition of a -Aminobutyric Acid Type A Receptor Partial Agonist in Humans

Departments of Pharmacokinetics, Pharmacodynamics, and Metabolism (C.L.S., M.G., A.D.V.), Clinical Pharmacology (K.V.), and Clinical Research Operations (A.H.B.), Pfizer Global Research and Development, Groton/New London Laboratories, Pfizer Inc., Groton, Connecticut

The metabolism and disposition of N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-indole-3-carboxamide (1), a potent subtype-selective partial agonist at the -aminobutyric acid type A receptor complex, were elucidated in humans following a p.o. dose of N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-[3-¹⁴C]indole-3-carboxamide monomethane-sulfonate ([¹⁴C]1). Overall, 1 was well tolerated, with approximately twice as much radioactivity excreted in feces (64.8 ± 13.3%) as in urine (28.4 ± 8.8%). Across subjects, the oral clearance of 1 was composed of both renal (10%) and metabolic (90%) components, with the biotransformation of 1 happening predominately via oxidative deamination to either 2-fluoro-4-[(4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carbonyl)-amino]-phenoxy acetic acid (2) or 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid [3-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-amide (3) and minimally by aliphatic hydroxylation and carbamate formation. Active renal secretion of 1 was observed as its unbound renal clearance was 6-fold greater than the glomerular filtration rate. Experiments using human hepatic in vitro systems were undertaken to better understand the enzyme(s) involved in the clinically observed oxidative biotransformation pathways. N-Dealkylation of 1, the principal metabolic route observed in vivo, was found to be predominately monoamine oxidase-B-mediated with the resulting putative aldehyde intermediate undergoing subsequent oxidation to 2 or reduction to 3.