Received for publication December 19, 2006.
Revised March 6, 2007.
Accepted for publication April 17, 2007.

METABOLISM AND DISPOSITION OF A SELECTIVE 7 NICOTINIC ACETYLCHOLINE RECEPTOR AGONIST IN HUMANS

Abstract

The metabolism and disposition of N-(3R)-1-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pyridine-5-carboxamide (1), an 7 nicotinic acetylcholinergic receptor agonist, were elucidated in humans (4 female, 4 male; all Caucasian) following an oral dose of [³H]1. Overall, 1 was well tolerated, with >94% of administered radioactivity excreted renally by 48 h post-dose; lyophilization of all urine and plasma samples confirmed ³H-stability within [³H]1. Across genders, 1 underwent low-to-moderate oral clearance comprised of both renal (67%) and metabolic (33%) components, with the biotransformation of 1 occurring predominately via oxidation of its furanopyridine moiety to carboxylic acid 2, and minimally by modification of its quinuclidine nitrogen to N-oxide 4 or N-glucuronide M5. Experiments using human in vitro systems were undertaken to better understand the enzyme(s) involved in the Phase I biotransformation pathways. The formation of 2 was found to be mediated by CYP2D6, a polymorphically expressed enzyme absent in 5-10% of Caucasians, while the generation of 4 was catalyzed by CYP2D6, FMO1 and FMO3. Interestingly, although no overall gender-related differences in excretory routes, mass recoveries, pharmacokinetics or metabolite profiles of 1 were evident, the observation of one of eight subjects (13%) showing disparate (relative to all other volunteers) systemic exposures to 1, and urinary and plasma quantitative profiles nearly devoid of 2 with highest levels of 1, seem consistent with both the identification of CYP2D6 as the only major recombinant CYP transforming 1 to 2 and the demographics of Caucasian CYP2D6 poor metabolizers. Data also reported herein suggest that 4 is generated predominately by renal FMO1 in humans.

Key words: clinical pharmacokinetics, CYP2D, drug development, drug disposition, extrahepatic drug metabolism, human pharmacokinetics, mass spectrometry, metabolite identification, renal elimination