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 la st doses in melanoma patients, who participated in a study run to asse ss tolerance over a long period of a treatment schedule of 13cisRA ass ociated with recombinant interferon a2a (rIFN-a2a). Melanoma patients with regional node metastases after radical surgery were randomized to be treated for 3 months with rIFN-a2a, 3 x 10(6) IU s.c. every other day, associated with oral 13cisRA at doses of 20 mg day(-1) (five pati ents) or 40 mg every other day (seven patients). Maximum 13cisRA blood concentrations usually occurred 4 h after drug administration, with a verage Values of 406 and 633 ng ml(-1) (i.e. 1.3 and 2.1 mu M) after t he 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 (AUC(0-48)) of 13c isRA did not change after multiple dosing, whereas the AUC(0-48) of it s major blood metabolite, 4-oxo-13-cis-retinoic acid, increased. Immed iately after 13cisRA treatment, retinol plasma levels started to decli ne and they reached the lowest Values (approximately 20% reduction) sh ortly after the time of maximum 13cisRA concentrations (i.e. 4-12 h af ter drug intake). Afterwards, values returned to baseline. The amount of retinol reduction in time was correlated with 13cisRA maximum conce ntrations.