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Research ArticleArticle

Using a Tritiated Compound to Elucidate Its Preclinical Metabolic and Excretory Pathways in Vivo: Exploring Tritium Exchange Risk

Christopher L. Shaffer, Mithat Gunduz, Bruce A. Thornburgh and Gwendolyn D. Fate
Drug Metabolism and Disposition September 2006, 34 (9) 1615-1623; DOI: https://doi.org/10.1124/dmd.106.010934
Christopher L. Shaffer
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Mithat Gunduz
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Bruce A. Thornburgh
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Gwendolyn D. Fate
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Abstract

The metabolism and excretion of N-(3R)-1-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pyridine-5-carboxamide (1), an agonist of the α7 nicotinic acetylcholinergic receptor, were determined in both Sprague-Dawley rats and beagle dogs using [3H]1. Initially, 3-tritio-furanopyridine 1 ([3H]1a) was evaluated in pilot mass balance studies by determining total radioactivity recovery and pharmacokinetics in lyophilized excreta and nonlyophilized plasma, respectively. Lower mass balance and much greater circulatory radioactivity exposures were observed in rats than in dogs, with urinary tritiated water (HTO) only detected in rats. The 133-h half-life in rats, possibly due to very slowly eliminated metabolites, was more likely attributable to HTO formed from [3H]1a because of site-specific chemical and/or metabolic 3H instability, which was confirmed by urinary HTO. In contrast, dog data supported 3H stability within [3H]1a. Conflicting cross-species data with [3H]1a suggested species-specific metabolic fates for 1, requiring a 3H form of 1 resistant to 3H loss in rats. Therefore, tritiation of 1 at its furanopyridine C7, a site predicted to be both chemically and metabolically stable, yielded 7-tritio-N-(3R)-1-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pyridine-5-carboxamide ditrifluoroacetate ([3H]1b), which allowed in both species the determination of all excretory pathways, total radioactivity pharmacokinetics, and major excretory and circulatory metabolites with complete radioactivity recovery without HTO generation. Definitive metabolite elucidation for 1 using [3H]1b confirmed the suspected species-dependent metabolic susceptibility for 3H loss from [3H]1a in rats, but not dogs, since the majority of rat metabolites resulted from furanopyridine biotransformation. The described studies explore the evaluation of tritium exchange risk from a mechanistic biotransformation perspective and highlight the need for careful deliberation when considering and designing 3H compounds for radiolabeled metabolism studies.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.010934.

  • ABBREVIATIONS: HTO, tritiated water; PK, pharmacokinetic(s); AUC, area under the plasma concentration-time curve; 1, N-(3R)-1-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pyridine-5-carboxamide (2E)-2-butanedioate; [3H]1a, 3-tritio-N-(3R)-1-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pyridine-5-carboxamide hydrochloride; [3H]1b, 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; 3, N-(3R)-1-azabicyclo[2.2.2]oct-3-ylcarbamoyl-5-hydroxypyridine-4-carboxylic acid; 4, N-(3R)-1-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pyridine-5-carboxamide-1-N-oxide; PGRD, Pfizer Global Research and Development; HPLC, high-performance liquid chromatography; DMSO, dimethyl sulfoxide; ESI, electrospray ionization; LSC, liquid scintillation counting; LC-MS/MS, liquid chromatography-tandem mass spectrometry; rcf, relative centrifugal force; LC tR, liquid chromatography retention time; CID, collision-induced dissociation.

  • ↵1 Current affiliation: Novartis Institutes for BioMedical Research, Department of Metabolism and Pharmacokinetics, Cambridge, MA.

    • Received May 3, 2006.
    • Accepted June 15, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (9)
Drug Metabolism and Disposition
Vol. 34, Issue 9
1 Sep 2006
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Research ArticleArticle

Using a Tritiated Compound to Elucidate Its Preclinical Metabolic and Excretory Pathways in Vivo: Exploring Tritium Exchange Risk

Christopher L. Shaffer, Mithat Gunduz, Bruce A. Thornburgh and Gwendolyn D. Fate
Drug Metabolism and Disposition September 1, 2006, 34 (9) 1615-1623; DOI: https://doi.org/10.1124/dmd.106.010934

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Research ArticleArticle

Using a Tritiated Compound to Elucidate Its Preclinical Metabolic and Excretory Pathways in Vivo: Exploring Tritium Exchange Risk

Christopher L. Shaffer, Mithat Gunduz, Bruce A. Thornburgh and Gwendolyn D. Fate
Drug Metabolism and Disposition September 1, 2006, 34 (9) 1615-1623; DOI: https://doi.org/10.1124/dmd.106.010934
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