5a-reductase inhibitors finasteride

Our second example of drugs that function as mechanism-based inactivators is the steroid 5a-reductase inhibitors finasteride and dutasteride. The mechanism of inactivation by these compounds is an interesting departure from the typical target enzyme covalent modification seen with most mechanism-based inactivators. 

Males with deficiency of the 5a-reductase isoenzyme do not develop acne, male pattern baldness, or enlarged prostates.274 The last fact was some of the impetus for development of the steroid 5a-reductase inhibitor finasteride, which is widely used to treat benign prostate enlargement 274/277/278 It is an enzyme-activated inhibitor in which the NADH reduces the C= C bond in the A ring, which is not in the same position as in the substrate. The resulting anion cannot become protonated but instead adds to the NAD+ as shown in Eq. 22-15. 

Lipophilic extracts of sabal fruit (Serenoa repens syn. Sabal seruulata) are used in the treatment of benign prostatic hyperplasia (BPH) (see Chapter 55). The hexane extract of the pulp and seed contains a complex mixture of free fatty acids and their esters, small quantities of phytosterols (such as [3-sitosterol), aliphatic alcohols, and polyprenic compounds. The efficacy of this extract was recently compared with that of the 5a-reductase inhibitor finasteride for 6 months, in a randomized, double-blind trial involving almost 1100 men with moderate BPH. Dwarf palm and finasteride reduced the International Prostate Symptom Score by 37 and 39% and increased urinary peak flow by 2.7 and 3.2 ml/sec, respectively. In contrast to finasteride, dwarf palm had little effect on prostate volume. 

K., Parlow, A.F., Miller, D.D. and Dalton, J.T. (2004) Comparison of the pharmacological effects of a novel selective androgen receptor modulator, the 5a-reductase inhibitor finasteride, and the antiandrogen hydroxyflutamide in intact rats new approach for benign prostate hyperplasia. Endocrinology, 145, 5420-5428. 

The testes and adrenal glands produce 90% and 10%, respectively, of circulating testosterone. Testosterone enters prostate cells, where predominantly type II 5a-reductase activates testosterone to dihydrotestosterone, which combines with a cytoplasmic receptor. The complex enters the nucleus and induces changes in protein synthesis which promote glandular tissue growth of the prostate. Thus, 5a-reductase inhibitors (e.g., finasteride and dutas-teride) directly interfere with one of the major etiologic factors of BPH. 

Clark, R.L., Antonello, J.M., Grossman, J.T., Wise, L.D., Anderson, C., Bagdon, W.J., Prahalada, S., MacDonald, J.S. and Robertson, R.T. (1990b). External genitalia abnormalities in male rats exposed in utero to finasteride, a 5a-reductase inhibitor. Teratology 42 91-100. 

Finasteride, the first 5a-reductase inhibitor, was introduced more than a decade ago. It competitively inhibits 5aR-2 but is only weakly active against... 

B. Finasteride is a 5a-reductase inhibitor, which essentially makes dihydrotestosterone unavailable to the prostate but does not reduce serum testosterone levels. The decreased prostatic levels of dihydrotestosterone frequently result in a size regression of the prostate, while the relatively normal testosterone levels minimize a depressed libido. Flutamide and spironolactone exhibit antiandrogen effects by competing for the androgen receptor ketoconazole inhibits testosterone synthesis and stanozolol is an oral anabolic androgen preparation. 

Ciotta L, Cianci A, Calogero AE, Palumbo MA, Marietta E, Sciuto A, Palumbo G. Clinical and endocrine effects of finasteride, a 5a-reductase inhibitor in women with idiopathic hirsutism. Fertil Steril 1995 64 299-306. 

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