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 alpha7 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.