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

Abstract

ABSTRACT:The metabolism and excretion of N-(3R) -

Metabolism and Disposition of a Selective α7 Nicotinic Acetylcholine Receptor Agonist in Humans

“…21% of total circulatory radioactivity, possibly necessitating its future pharmacokinetic characterization in humans as a metabolite-monitoring strategy (Baillie et al, 2002). All human metabolites, except M5, were observed previously (Shaffer et al, 2006) in rats and dogs, confirming these as appropriate toxicological species. Although M5 was not observed in these animals, its minor quantities (Յ3%) and conjugative nature, indicative of a highly polar compound with a low volume of distribution and innocuous pharmacology, make it of little concern from a safety perspective (Smith and Obach, 2005).…”

“…This observation, supplemented by both the FMO1-mediated formation rate of 4 being 9 times faster than that of FMO3 and the greater quantity of 4 in urine versus plasma (Table 5) with no fecal elimination, strongly suggests, but does not prove, that 4 is generated by renal FMO1 in humans. These suspected FMO1-related in vitro data were borne out in vivo (Shaffer et al, 2006), inasmuch as rats and dogs converted 1 to 4 in greater amounts (11% and 63% of total dose in urine, respectively) than did humans (8%). Reaction phenotyping studies using the recombinant enzymes of the major drug-metabolizing human P450s suggest that the formation of 2, arising from biotransformation of the furanopyridine within 1, is mediated by CYP2D6, a polymorphically expressed enzyme absent in ca.…”

“…1). Although prior work (Shaffer et al, 2006) demonstrated the in vivo chemical and metabolic stability of the tritium atom within [ 3 H]1 in both rats and dogs, all collected human urine and plasma were nonetheless subjected to lyophilization to confirm empirically the expected tritium inertness. Elucidation of the clearance routes, metabolites, postdose; feces were collected predose and as passed at 24-or 48-h intervals for 8 days postdose.…”

Human radiolabeled mass balance studies: objectives, utilities and limitations

“…Unfortunately, the pros of the tritium use are outweighed by the cons, notably, the lack of biological stability and isotopic effect (switching biotransformation pathway due to reaction kinetics) [23]. When a tritium-labeled molecule is involved in biotransformation, the tritium label can be displaced from its position and converted into tritiated water [24]. In turn water can be excreted via urine and could be lost during sample work up and could complicate establishing the mass balance.…”

Applications of Quantitative Whole‐Body Autoradiography (QWBA) in Drug Discovery and Development

“…Radiolabeled drugs have been widely used in drug discovery and development studies since radioactivity can easily be detected and quantifi ed using liquid scintillation techniques, quantitative whole -body autoradiography ( QWBA ), and other methods (Shaffer et al, 2006 ;Christopher et al, 2008 ;Wang et al, 2006Wang et al, , 2010aZhang et al, 2009 ). Tissue distribution studies with radiolabeled drugs in animals are important in drug discovery and development and provide distribution and pharmacokinetic information of the test drug or its metabolites in animal tissues or organs (Igari et al, 1982 ;Xiang et al, 2004 ;He et al, 2008 ).…”