A Mass Balance Study to Evaluate the Biotransformation and Excretion of [14C]‐Triamcinolone Acetonide following Oral Administration

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Abstract
The principle objective of this study was to characterize the absorption, metabolism, and disposition of orally administered [14C]‐triamcinolone acetonide. Six healthy male subjects each received a single 100 μCi (≅800 μg) oral dose of [14C]‐triamcinolone acetonide. Plasma, urine, and fecal samples were collected at selected times and analyzed for triamcinolone acetonide and [14C]‐derived radioactivity. Plasma protein binding of triamcinolone acetonide was also determined. Metabolite profiling and identification were carried out in plasma and excreta. Principle metabolites were assessed for activity with in vitro anti‐inflammatory models. [14]‐triamcinolone acetonide was found to be systemically absorbed following oral administration. The presystemic metabolism and clearance of triamcinolone acetonide were extensive, with only a small fraction of the total plasma radioactivity being made up of triamcinolone acetonide. Little to no parent compound was detected in the plasma 24 hours after administration. Most of the urinary and fecally [14C]‐derived radioactivity was also excreted within 24 and 72 hours postdose, respectively. Mean plasma protein binding of triamcinolone acetonide was constant, predictable, and a relatively low 68% over a 24‐fold range of plasma concentrations. Three principle metabolites of triamcinolone acetonide were profiled in plasma, urine, and feces. These metabolites were identified as 6β‐hydroxy triamcinolone, 21‐carboxylic acid triamcinolone acetonide, and 6β‐hydroxy‐21‐oic triamcinolone acetonide. All three metabolites failed to show any concentration‐dependent effects in anti‐inflammatory models evaluating IL‐5‐sustained eosinophil viability and IgE‐induced basophil histamine release.