Disposition and metabolism of finasteride in dogs.

Finasteride (FIN) is a potent 5 alpha-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 B alpha 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 Cmax 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 Cmax 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.

Biotransformation of finasteride (MK-0906) by Selenastrum capricornutum (green algae).

Finasteride (MK-0906), a drug used for the treatment of benign prostatic hyperplasia, is a highly specific inhibitor of steroid 5 alpha-reductase, an enzyme that converts testosterone (T) to dihydrotestosterone (DHT) in animals and humans. In a study to evaluate the effect of finasteride on the growth of green alga, Selenastrum capricornutum, the parent drug was not detected by HPLC in the posttreatment (14 day) samples, suggesting complete biotransformation. Thermospray LC/MS, followed by NMR analysis, indicated that the major algal metabolite was 11 alpha-hydroxy-finasteride. This metabolite has negligible in vitro bioactivity against human prostatic 5 alpha-reductase; its potency is only 2% that of finasteride. The primary metabolite of finasteride produced by the green alga involved a biotransformation not previously observed in mammalian and human studies. The green alga effectively deactivates the drug, thereby mitigating any potential environmental impact.

Disposition and pharmacokinetics of [14C]finasteride after oral administration in humans.

The disposition of [14C]finasteride, a competitive inhibitor of steroid 5 alpha-reductase, was investigated after oral administration of 38.1 mg (18.4 microCi) 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 [14C]finasteride to plasma protein was extensive (91.3 to 89.8%), with a trend suggesting concentration dependency (range 0.02 to 2 micrograms/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.(ABSTRACT TRUNCATED AT 250 WORDS)

High-performance liquid chromatographic determination of N-(2-methyl-2-propyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide, a 4-azasteroid, in human plasma from a phase I study.

A sensitive and selective high-performance liquid chromatographic method has been developed for the quantitative determination of N-(2-methyl-2-propyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (I) in human plasma. I, a 5 alpha-reductase inhibitor and a potential therapeutic agent for benign prostatic hyperplasia, is a member of the family of compounds referred to as the 4-azasteroids. The 4-N-methyl analogue of the drug was used as the internal standard and calibration curves were developed at two levels of sensitivity to cover a large dynamic range of plasma concentrations. Drug was isolated from biological fluids with a solid-phase C18 extraction column; the analyte was further purified by adsorption and desorption from a second extraction column (CN cartridge). Evaluation of the isolation method revealed that it was reproducible and drug recoveries equalled ca. 90%. Chromatography was carried out on a C8 column (5 micron) with ultraviolet detection at 210 nm. The detection limit was ca. 10 ng/ml for I. Human plasma levels are reported for I following single-dose oral administration of 50,200 and 400 mg of drug; urinary excretion data are reported for a single volunteer given 400 mg of I.

Immunological evidence that inactive renin is prorenin.

Antibody raised to a synthetic dodecapeptide, corresponding to the C-terminal portion of the human renin pro-segment, was tested for its ability to recognize highly purified human inactive or active (mature) renins; immune complexes were detected by precipitation with protein A-Sepharose. Serial antibody dilutions caused identical binding of renal or plasma inactive renins but failed to bind active renin. In contrast, antibody to active renin recognized both active and inactive forms. Reversible acid activation of inactive renin enhanced its binding to the anti-prorenin antibody, whereas irreversible trypsin activation significantly reduced binding. Binding was abolished following prolonged exposure to trypsin or if inactive renin was acidified prior to trypsin treatment. These results indicate that inactive renin shares immunochemical determinants with prorenin; they suggest that acidification alters the conformation of the pro-segment and that trypsin can convert the molecule both to fully mature renin and to intermediate form(s).