Effects of steroid 5alpha-reductase inhibitor ONO-9302 and anti-androgen allylestrenol on the prostatic growth, and plasma and prostatic hormone levels in rats.
ONO-9302 [epristeride; (-)-17beta-(tert-butylcarbamoyl)androsta-3,5-diene-3-carboxy lic acid] is a novel inhibitor of steroid 5alpha-reductase. We studied in vitro and in vivo effects of ONO-9302 on the rat prostatic tissue in comparison with those of the anti-androgen allylestrenol. ONO-9302 inhibited the rat prostatic enzyme with an IC50 value of 11 nM, whereas allylestrenol was about 80,000-fold less potent. The growth of ventral prostate, which was induced by the subcutaneous injection of testosterone propionate in the castrated rats, was significantly reduced by ONO-9302 at oral doses of 1-100 mg/kg/day. Allylestrenol showed a significant effect only at a dose of 100 mg/kg/day. In mature male rats, ONO-9302 significantly reduced the ventral prostate weight at doses of 10-100 mg/kg/day and decreased prostatic 5alpha-dihydrotestosterone (DHT) content associated with a rise in testosterone (T) content at doses of 0.1-100 mg/kg/day. Plasma hormone levels (i.e., T, DHT, luteinizing hormone (LH) and follicle stimulating hormone (FSH)) were not altered significantly. Allylestrenol significantly reduced the ventral prostate weight at doses of 10-100 mg/kg/day. However, unlike ONO-9302, allylestrenol reduced both the prostatic DHT and T contents and also lowered plasma T, DHT, LH and FSH levels at a dose of 30 mg/kg/day. These results suggest that ONO-9302 reduces the prostatic growth by inhibiting the conversion of T to DHT in the prostate without lowering blood T level unlike anti-androgen drugs.
Yasuda
N
N
Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
Fujino
K
K
Shiraji
T
T
Nambu
F
F
Kondo
K
K
D058891:5-alpha Reductase Inhibitors; D000500:Allylestrenol / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005640:Follicle Stimulating Hormone / Q000097:blood*; D007986:Luteinizing Hormone / Q000097:blood*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D045167:Progesterone Congeners / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000033:anatomy & histology / Q000187:drug effects; D013739:Testosterone / Q000378:metabolism* / Q000494:pharmacology
D058891:5-alpha Reductase Inhibitors; D059002:Androgen Receptor Antagonists; D000730:Androstadienes; D004791:Enzyme Inhibitors; D045167:Progesterone Congeners; C072547:epristeride; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D000500:Allylestrenol