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Finasteride is a synthetic 4-azasteroid that is a specific competitive inhibitor of 5 alpha-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone (DHT). It has no binding affinity for androgen receptor sites and itself possesses no androgenic, antiandrogenic, or other steroid hormone-related properties. It is well absorbed after oral administration, with absolute bioavailability in humans of 63% (range 34-108%). The mean time to maximum concentration is 1-2 hours, and it is approximately 90% plasma protein bound. The elimination half-life averages 6-8 hours. The agent is metabolized to a series of five metabolites, of which two are active and possess less than 20% of the 5 alpha-reductase activity of finasteride. Little is known about potential drug interactions, although they appear to be minimal and not clinically relevant. The drug is indicated for the treatment of symptomatic benign prostatic hyperplasia. Its efficacy in regression of prostate gland enlargement is rapid and predictable, although correlation with subsequent improvement in urinary flow and symptoms is highly variable. Dosages of 0.5-100 mg/day regress prostate enlargement; the recommended dosage is 5 mg once/day. Finasteride may hold promise for other DHT-mediated disorders such as acne, facial hirsutism, frontal lobe alopecia, and prostate cancer, but its use in these conditions remains investigational. The frequency of adverse drug events is low, with the most common side effects being impotence, decreased libido, and decreased volume of ejaculate. No reports of intentional overdose have been reported, and dosages of up to 80 mg/day for 3 months have been taken without adverse effect.

The pharmacology and pharmacokinetics of finasteride are reviewed, and finasteride's clinical efficacy, adverse effects, and dosage in patients with benign prostatic hyperplasia (BPH) are described. Finasteride is a member of a new class of medications, the azasteroids, that have antiandrogenic activity limited to certain tissues, including the prostate gland. Finasteride inhibits the activity of 5 alpha-reductase, the enzyme necessary for converting testosterone to dihydrotestosterone in the prostate and other tissues. BPH is androgen dependent, and dihydrotestosterone is necessary for the hyperplasia to occur. Finasteride is well absorbed after oral administration; peak plasma concentration is reached in as little as one hour. Finasteride is approximately 90% bound to plasma proteins, is widely distributed, and is extensively metabolized by the liver. In clinical studies, finasteride has been effective in decreasing prostatic volume, increasing urinary flow rate, and decreasing the obstructive and irritative symptoms of BPH. Because of the heterogeneity of BPH, however, treatment is successful in only one third to one half of patients. Finasteride's adverse effects include decreased libido, ejaculatory disorders, and effects on prostate-specific antigen. The recommended dosage of finasteride is 5 mg/day orally. Therapy should be continued for at least six months before the clinical response is evaluated. Finasteride provides a pharmacologic alternative to surgery in patients with BPH.

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)

The hormonal effects following the acute (single dose) administration of a 4-azasteroid inhibitor of 5 alpha-reductase (MK-906) were evaluated in 10 healthy male volunteers. Marked suppression of serum dihydrotestosterone (DHT) was observed after the administration of single doses as low as 12.5 mg. The mean percent decrease in DHT at 24 hours in the group treated with a single 25-mg dose was 56% +/- 10% compared with the baseline. The suppression of plasma DHT levels continued for up to 72 hours. This study demonstrates that administration of single oral doses (12.5 to 400 mg) of MK-906 results in a significant decrease in the conversion of testosterone to DHT.

A high-performance liquid chromatographic (HPLC) method with ultraviolet detection for the determination of a novel 4-aza-steroidal inhibitor of 5 alpha-reductase in human plasma has been developed. The assay is based on a single solid-phase extraction and an efficient HPLC separation on two analytical columns in series. The assay has been fully validated and used to support Phase II and III clinical pharmacokinetic studies. The lowest limit of quantification was found to be at 1 ng/ml and allowed pharmacokinetic evaluation of the drug at doses down to 5 mg.

The pharmacokinetics and biochemical efficacy of N-(2-methyl-2-propyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide (I) were evaluated in healthy male volunteers after single and multiple oral administration. The mean times to reach peak plasma concentrations (Tmax) of (I) at doses of 5, 10, 20, 50 and 100 mg ranged from 1.8 to 2.8 h, and the corresponding mean peak plasma concentrations (Cmax) were 38.1, 81.5, 147.1, 442.0 and 835.5 ng/ml, respectively. The drug disappeared from the systemic circulation with half-lives (t1/2) of 4.7-7.1 h. The mean values of the area under the curve (AUC0-24) and Cmax increased linearly in a dose-dependent manner. After multiple oral administration of (I) (10 mg/d) for 7 days, Cmax and AUC increased slightly during administration, however, there were no significant differences between day 4 and day 7. Although there were large intersubject differences in the 24 h plasma levels after each dosing, no accumulation of (I) occurred after 7 days dosing. Serum 5-alpha-dihydrotestosterone (DHT) was markedly reduced at all dose levels. The mean serum levels of DHT at 24 h post-dosing decreased to 27-42% of that before dosing. On the other hand, the serum testosterone (T) did not change significantly. After multiple administration of (I), serum DHT was significantly reduced and remained suppressed for up to 7 days after the final dosing.

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.