Abstract
The metabolism and disposition of N-(3R)-1-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pyridine-5-carboxamide (1), an α7 nicotinic acetylcholinergic receptor agonist, were elucidated in humans (4 female, 4 male; all white) after an oral dose of [3H]1. Overall, 1 was well tolerated, with >94% of administered radioactivity excreted renally by 48 h postdose; lyophilization of all urine and plasma samples confirmed 3H stability within [3H]1. Across genders, 1 underwent low-to-moderate oral clearance comprising both renal (67%) and metabolic (33%) components, with the biotransformation of 1 occurring predominantly 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 1 biotransformation pathways. The formation of 2 was found to be mediated by CYP2D6, a polymorphically expressed enzyme absent in 5 to 10% of white people, whereas the generation of 4 was catalyzed by CYP2D6, FAD-containing monooxygenase 1 (FMO1), and FMO3. It is of interest that, 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 the highest levels of 1, seem consistent with both the identification of CYP2D6 as the only major recombinant cytochrome P450 transforming 1 to 2 and the demographics of white CYP2D6 poor metabolizers. Data also reported herein suggest that 4 is generated predominantly by renal FMO1 in humans.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.014449.
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ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; 1, N-(3R)-1-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pyridine-5-carboxamide (2E)-2-butanedioate; GTS-21, 3-[(2,4-dimethoxy)benzylidene]anabaseine; [3H]1, 7-tritio-N-(3R)-1-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pyridine-5-carboxamide ditrifluoroacetate; 2, N-(3R)-1-azabicyclo[2.2.2]oct-3-ylcarbamoyl-5-hydroxypyridin-4-yl-acetic acid; 4, N-(3R)-1-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pyridine-5-carboxamide-1-N-oxide; P450, cytochrome P450; FMO, FAD-containing monooxygenase; HTO, tritiated water; LSC, liquid scintillation counting; LC-MS/MS, liquid chromatography-tandem mass spectrometry; HPLC, high performance liquid chromatography; AUC, area under the plasma concentration-time curve; kel, elimination rate constant; rcf, relative centrifugal force; MRM, multiple-reaction monitoring; HLM, human liver microsome; HKM, human kidney microsome; LC tR, liquid chromatography retention time; CID, collision-induced dissociation; PGRD, Pfizer Global Research and Development; MeCN, acetonitrile (methyl cyanide); CL, clearance; GFR, glomerular filtration rate; RLM, rat liver microsome; DLM, dog liver microsome; PM, poor metabolizer.
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↵1 Current affiliation: Novartis Institutes for BioMedical Research, Department of Metabolism and Pharmacokinetics, Cambridge, Massachusetts.
- Received December 19, 2006.
- Accepted April 17, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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