0090-9556/97/2501-0100-0109$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 1

Disposition and Metabolism of Finasteride in Dogs

J. R. Carlin, P. Christofalo, B. H. Arison, R. E. Ellsworth, A. Rosegay, R. R. Miller, S. H. L. Chiu, and W. J. A. Vandenheuvel

Department of Drug Metabolism, Merck Research Laboratories

Finasteride (FIN) is a potent 5-reductase inhibitor that has shown clinical success in treating men with benign prostatic hyperplasia. In the study of biological effects and metabolism of FIN in animals, the dog serves as the primary modality. This study was conducted to determine the pharmacokinetics and fate of FIN after oral administration of single doses of [¹⁴C]FIN to dogs at 10 and 80 mg/kg (N = 2 and 3, respectively), and also after intravenous infusion at 5 mg/kg (N = 2). Plasma, urine, and feces were analyzed for total ¹⁴C content. Parent drug and metabolites in plasma and excreta were measured by HPLC/UV/radioassay and identified by NMR spectroscopy and MS. FIN was subject to extensive biotransformation before excretion. Structures were determined for the major metabolites in plasma, urine, and feces. The primary metabolic events for FIN were hydroxylation of the t-butyl side chain to give hydroxymethyl-FIN (metabolite I), which is oxidized further to form the carboxylic acid derivative (metabolite IV), and hydroxylation at positions 6 and 15. Terminal half-life of FIN after the intravenous dose was 3.4 hr. Plasma clearance and volume of distribution at steady-state were 4.8 ml/min/kg and 1.1 liter/kg. Dogs showed rapid absorption after oral administration of the low dose, with C_max reached in the 1-2 hr; bioavailability was estimated to be >90%. After either dosing route, 45% of the plasma radioactivity (as represented by AUC) was parent drug, 43% was metabolite I, and 1% was metabolite IV. After oral administration, the 80 mg/kg dose was absorbed slowly, with the highest levels of radioactivity in plasma reached in 4-30 hr. Average C_max value for FIN and metabolite I increased in a dose-related, but nonproportional, manner. Compared with the 10 mg/kg dose, it seems the higher dose was reasonably well-absorbed, as indicated by the nearly proportional increase of AUC values of total radioactivity and FIN. Composition of plasma metabolites observed at the 80 mg/kg dose level was similar to that observed previously for the low dose, suggesting that an increase in plasma exposure was effected in dogs receiving FIN at 80 mg/kg in toxicity studies. Most of the administered radioactivity was recovered in feces after all doses. Little of the intravenous and low oral doses, but >50% of the 80 mg/kg oral dose, was excreted as intact FIN, suggesting that metabolism might have been saturated at the high dose.