Finasteride has been shown to be a
Finasteride has been shown to be a mechanism-based inhibitor of 5AR-2 . Finasteride acts as an alternate substrate for 5AR-2 and is initially bound in an extremely stable enzyme-bound NADP-dihydrofinasteride adduct which is ultimately processed to dihydrofinasteride. The NADP-dihydrofinasteride adduct is a potent bisubstrate analog inhibitor with a dissociation constant K≤1×10−13M, making it one of the most potent non-covalently bound inhibitors known. Finasteride is also an inhibitor of 5AR-1, but the dihydrofinasteride adduct is formed with a much smaller rate constant compared to 5AR-2 (Table 1B). Finasteride was the first steroidal 5ARI approved by the US Food and Drug Administration (USFDA) in 1992 for treatment of BPH. It reduces the levels of Macitentan mg DHT by 70–90%, thereby reducing prostate size , .
Dutasteride is a specific dual inhibitor of 5AR. Enzymology studies indicate it is a potent irreversible competitive inhibitor of both human 5AR-1 and -2 , . Dutasteride forms a stable complex with both isoenzymes which has a slow rate of dissociation (Table 1B). Dutasteride is approximately 60 times more potent than finasteride and was approved in 2002 by the USFDA for use in treatment of BPH. Dutasteride reduces DHT levels by >90% after 1 year of oral administration, resulting in a smaller prostate volume .
Finasteride and dutasteride are the only two steroidal drugs in use clinically, although there are others, such as epristeride, currently in clinical trials. As summarized in Table 1A, Table 1B, finasteride and dutasteride have distinct properties which may suggest their optimal use in treating prostate disease, but it has not yet been determined whether there is a significant difference in clinical applications/outcomes between the two . A number of non-steroidal 5ARIs have also been developed as mimics of steroidal inhibitors, but none have been brought to clinical use .
5ARIs in the treatment of BPH BPH is a progressive disease, with increasing prostate volume leading to increased LUTS resulting from pressure on the urethra and accompanying decreased urinary flow. BPH is prevalent among aging men and affects up to 90% of men by the age of 80 or older, making this a vital healthcare issue with associated economic implications . Medical treatment is thus focused on relieving LUTS and avoiding disease progression which could eventually result in complications such as acute urinary retention (AUR) and/or surgery. Both 5AR-1 and -2 isoenzymes are significantly over-expressed in BPH tissue as compared to normal prostate tissue, with 5AR-2 being the predominant form . Thus, initial treatment options currently available for men with BPH-LUTS are to use either a 5ARI, or an α1-adrenoreceptor antagonist (alpha-blocker) such as doxazosin or tamsulosin, or a combination of the two. While finasteride is the most widely studied 5ARI, there have been a number of clinical studies demonstrating that both finasteride and dutasteride are effective in treating BPH-LUTS either as monotherapy or in combination with an alpha blocker. In 1998 the Proscar Long-term Efficacy and Safety Study (PLESS) verified the effectiveness of finasteride treatment alone in a trial involving 3040 men treated with placebo or 5mg finasteride daily for a period of four years . Significant reductions in the number of men experiencing AUR or ultimately requiring surgery were apparent within 4 months. For men completing the study, total prostate volume (TPV) decreased and improved symptom scores were observed in the finasteride group. Combined data from three large ARIA studies (ARIA 3001 and 3002 in the US, ARIA 3003 in 19 countries, with over 4000 men) , demonstrated the effectiveness of dutasteride in reducing prostate size and LUTS. Treatment with dutasteride reduced serum DHT by 90.2% at 24 months, followed by a rapid reduction in TPV. Dutasteride reduced the risk of AUR or eventual surgical intervention by 50% within two years. This study confirmed the hypothesis that using a dual 5ARI like dutasteride to achieve nearly complete suppression of serum DHT levels can halt the progression of BPH.