DISPOSITION AND PHARMACOKINETICS OF [C-14] FINASTERIDE AFTER ORAL-ADMINISTRATION IN HUMANS

The disposition of [C-14]finasteride, a competitive inhibitor of steroid 5-alpha-reductase, was investigated after oral administration of 38.1 mg (18.4-mu-Ci) of drug in six healthy volunteers. Plasma, urine, and feces were collected for 7 days and assayed for total radioactivity. Concentrations of finasteride and its neutral metabolite, omega-hydroxyfinasteride (monohydroxylated on the t-butyl side chain), in plasma and urine were determined by HPLC assay. Mean excretion of radioactivity equivalents in urine and feces equaled 39.1 +/- 4.7% and 56.8 +/- 5.0% of the dose, respectively. The mean peak plasma concentrations reached for total radioactivity (ng equivalents), finasteride, and omega-hydroxyfinasteride were 596.5 +/- 88.3, 313.8 +/- 99.4, and 73.7 +/- 11.8 ng/ml, respectively, at approximately 2 hr; the mean terminal half-life for drug and metabolite was 5.9 +/- 1.3 and 8.4 +/- 1.7 hr, respectively. Of the 24-hr plasma radioactivity, 40.9% was finasteride, 11.8% was the neutral metabolite, and 26.7% was characterized as an acidic fraction of radioactivity. Binding of [C-14]finasteride to plasma protein was extensive (91.3 to 89.8%), with a trend suggesting concentration dependency (range 0.02 to 2-mu-g/ml). Little of the dose was excreted in urine as parent (0.04%) or omega-hydroxyfinasteride (0.4%). Urinary excretion of radioactivity was largely in the form of acidic metabolite(s)-18.4 +/- 1.7% of the dose was eliminated as the omega-monocarboxylic acid metabolite. Finasteride was scarcely excreted unchanged in feces. In humans, finasteride is extensively metabolized through oxidative pathways. As both the omega-hydroxyfinasteride and the monocarboxy metabolite possess in vitro bioactivity, it is possible that the metabolites could contribute to the pharmacologic effect of finasteride. Demonstrating the biochemical efficacy of finasteride, plasma 5-alpha-dihydrotestosterone levels were markedly reduced: the mean percentage change from baseline at 24 hr post-dose was 76.7%.