title: Metabolism and disposition of a gamma-aminobutyric acid type A receptor partial agonist in humans.
abstract: 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 gamma-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-(14)C]indole-3-carboxamide monomethane-sulfonate ([(14)C]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 (< or =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.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton/New London Laboratories, Pfizer Inc., Eastern Point Road, MS 8220-4186, Groton, CT 06340, USA. christopher.l.shaffer@pfizer.com
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Shaffer
authors.forename: Mithat
authors.initials: M
authors.lastname: Gunduz
authors.forename: Alfin D
authors.initials: AD
authors.lastname: Vaz
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.forename: Aaron H
authors.initials: AH
authors.lastname: Burstein
mesh_terms: D000293:Adolescent; D000328:Adult; D018755:GABA Agonists / Q000737:chemistry* / Q000378:metabolism*; D058785:GABA-A Receptor Agonists; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000502:physiology; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D011963:Receptors, GABA-A / Q000378:metabolism*; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A