Pharmacokinetics and pharmacodynamics of 9-cis-retinoic acid in healthy men

J Clin Pharmacol. 1997 Jul;37(7):566-74. doi: 10.1002/j.1552-4604.1997.tb04338.x.

Abstract

A double-blind, placebo-controlled, randomized study using single ascending oral doses of 5 mg, 15 mg, 40 mg, 80 mg, and 150 mg of 9-cis-retinoic acid was performed to assess the single-dose pharmacokinetics, tolerability, and pharmacodynamic effects of 9-cis-retinoic acid in healthy men. Forty participants received treatment (six taking the active treatment and two taking placebo for each dose level). The pharmacokinetics of 9-cis-retinoic acid were linear over the dose range studied. Peak plasma concentrations were achieved within 3 to 4 hours on average. The half-life was in the range of 1.3 to 2.4 hours. Metabolism was the major pathway of elimination. 4-Oxo-9-cis-retinoic acid, one of four metabolites measured, which included all-trans-retinoic acid and 13-cis-retinoic acid, was the main metabolite in plasma, achieving peak plasma levels of 41% to 83% of those of 9-cis-retinoic acid. Dose-/concentration-dependent reductions of retinol in plasma, with a maximum of 30% from baseline, were observed 24 hours after administration. Baseline levels were recovered after 5 days. Concentrations of retinol binding protein remained unchanged. Overall, the drug was well tolerated at all dose levels. Adverse events observed were consistent with findings of other retinoids (all-trans-retinoic acid and 13-cis-retinoic acid) and included headache and xeroderma at high dose levels.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Alitretinoin
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology*
  • Double-Blind Method
  • Humans
  • Isotretinoin / blood
  • Male
  • Retinol-Binding Proteins / analysis
  • Retinol-Binding Proteins, Plasma
  • Tretinoin / adverse effects
  • Tretinoin / analogs & derivatives
  • Tretinoin / blood
  • Tretinoin / pharmacokinetics*
  • Tretinoin / pharmacology*
  • Vitamin A / blood

Substances

  • Antineoplastic Agents
  • Retinol-Binding Proteins
  • Retinol-Binding Proteins, Plasma
  • Vitamin A
  • Alitretinoin
  • 4-oxoretinoic acid
  • Tretinoin
  • Isotretinoin