title: Pharmacodynamic analysis of steroid 5alpha-reductase inhibitory actions of Z-350 in rat prostate.
abstract: The pharmacodynamics of (S)-4-[3-[4-[1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]propoxy]benzoyl]indole-1-yl] butyric acid hydrochloride (Z-350), which has alpha(1)-adrenoceptor antagonistic and steroid 5alpha-reductase inhibitory effects, were investigated in rats. The disposition of Z-350 was a function of linear kinetics at doses from 1 to 30 mg/kg; the bioavailability was calculated to be 65.2%. The inhibition of 5alpha-reductase was dependent on the concentration of Z-350 in plasma and in the prostate. Analysis of the relationship between the concentration in the prostate and the inhibition seen after a single oral administration showed that the Hill constant was almost 1.0 and EC(50)(n(H)) was 47.4 ng/g of tissue; these parameters did not change after multiple administration. Z-350 inhibited 5alpha-reductase 1 h after oral administration at a dose of 3 mg/kg; maximum inhibition was observed after 2-4 h, and the inhibition (%) was maintained for 24 h after oral administration.
authors.affiliation: Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., 2512-1 Oshikiri, Konan-machi, Osato-gun, Saitama 360-0111, Japan. shigeru-furuta@zeria.co.jp
authors.forename: S
authors.initials: S
authors.lastname: Furuta
authors.forename: Y
authors.initials: Y
authors.lastname: Fukuda
authors.forename: T
authors.initials: T
authors.lastname: Sugimoto
authors.forename: H
authors.initials: H
authors.lastname: Miyahara
authors.forename: E
authors.initials: E
authors.lastname: Kamada
authors.forename: H
authors.initials: H
authors.lastname: Sano
authors.forename: Y
authors.initials: Y
authors.lastname: Fukuta
authors.forename: M
authors.initials: M
authors.lastname: Takei
authors.forename: T
authors.initials: T
authors.lastname: Kurimoto
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics*; D011467:Prostate / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D010879:Piperazines; C121225:Z 350; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase