Pharmacokinetics and effects on plasma retinol concentrations of 13-cis-retinoic acid in melanoma patients

The pharmacokinetics of 13-cis-retinoic acid (13cisRA) and its effects on retinol plasma levels were investigated after the first and the last doses in melanoma patients, who participated in a study run to assess tolerance over a long period of a treatment schedule of 13cisRA associated with recombinant interferon α2a (rIFN-α2a). Melanoma patients with regional node metastases after radical surgery were randomized to be treated for 3 months with rIFN-α2a, 3 x 10⁶ IU s.c. every other day, associated with oral 13cisRA at doses of 20 mg day^-1 (five patients) or 40 mg every other day (seven patients). Maximum 13cisRA blood concentrations usually occurred 4 h after drug administration, with average values of 406 and 633 ng ml^-1 (i.e. 1.3 and 2.1 μM) after the 20 and 40 mg dose respectively. The average half-life (t(1/2)) was approximately 30 h. The maximum concentration, the t(1/2) and the area under the concentration-time curves from 0 to 48 h (AUG_0-48) of 13cisRA did not change after multiple dosing, whereas the AUG_0-48 of its major blood metabolite, 4-oxo-13-cis-retinoic acid, increased. Immediately after 13cisRA treatment, retinol plasma levels started to decline and they reached the lowest values (approximately 20% reduction) shortly after the time of maximum 13cisRA concentrations (i.e. 4-12 h after drug intake). Afterwards, values returned to baseline. The amount of retinol reduction in time was correlated with 13cisRA maximum concentrations.