Received for publication November 15, 2007.
Revised December 19, 2007.
Accepted for publication January 3, 2008.

METABOLISM AND DISPOSITION OF A GABA_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 GABA_A receptor complex, were elucidated in humans following an oral dose of [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 comprised of both renal (10%) and metabolic (90%) components, with the biotransformation of 1 happening predominately via oxidative deamination to either carboxylic acid 2 or alcohol 3, and minimally by aliphatic hydroxylation and carbamate formation. Active renal secretion of 1 was observed as its unbound renal clearance was six-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 MAO-B-mediated with the resulting putative aldehyde intermediate undergoing subsequent oxidation to 2 or reduction to 3.

Key words: clinical pharmacokinetics, drug clearance, drug disposition, human pharmacokinetics, mass spectrometry, metabolite identification, structure elucidation