TY - JOUR T1 - Metabolism and Disposition of a γ-Aminobutyric Acid Type A Receptor Partial Agonist in Humans JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 655 LP - 662 DO - 10.1124/dmd.107.019760 VL - 36 IS - 4 AU - Christopher L. Shaffer AU - Mithat Gunduz AU - Alfin D. Vaz AU - Karthik Venkatakrishnan AU - Aaron H. Burstein Y1 - 2008/04/01 UR - http://dmd.aspetjournals.org/content/36/4/655.abstract N2 - 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 γ-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. ER -