Pharmacodynamic analysis of steroid 5alpha-reductase inhibitory actions of Z-350 in rat prostate

Eur J Pharmacol. 2001 Aug 24;426(1-2):105-11. doi: 10.1016/s0014-2999(01)01208-0.

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.

MeSH terms

  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / metabolism
  • 5-alpha Reductase Inhibitors*
  • Administration, Oral
  • Animals
  • Area Under Curve
  • Enzyme Inhibitors / pharmacokinetics*
  • Indoles / blood
  • Indoles / pharmacokinetics*
  • Male
  • Metabolic Clearance Rate
  • Piperazines / blood
  • Piperazines / pharmacokinetics*
  • Prostate / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors

Substances

  • 5-alpha Reductase Inhibitors
  • Enzyme Inhibitors
  • Indoles
  • Piperazines
  • Z 350
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase