Pharmacokinetics and pharmacodynamics of 9-cis-retinoic acid in healthy men.
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.
Weber
C
C
F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Dumont
E
E
D000328:Adult; D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004311:Double-Blind Method; D006801:Humans; D015474:Isotretinoin / Q000097:blood; D008297:Male; D012177:Retinol-Binding Proteins / Q000032:analysis; D054839:Retinol-Binding Proteins, Plasma; D014212:Tretinoin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014801:Vitamin A / Q000097:blood
D000970:Antineoplastic Agents; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; D014801:Vitamin A; D000077556:Alitretinoin; C002202:4-oxoretinoic acid; D014212:Tretinoin; D015474:Isotretinoin