Pharmacology of 13-c/s-Retinoic Acid in Humans1

Vitamin A and its analogs (retinoids) have shown great prom ise for the chemoprevention of cancer as well as being a possible new class of chemotherapeutic agents. A Phase I and II trial of 13-c/s-retinoic acid in advanced cancers was initiated, and the clinical pharmacology of the drug was studied. All patients received p.o. 13-c/s-retinoic acid starting at 0.5 mg/ kg/day, escalating over 4 weeks to a maximum dose of 8 mg/ kg/day in divided doses. Although there was a linear correla tion of plasma concentration with dose escalation, large interindividual variations in peak plasma concentrations were noted. At the maximum drug dose, the mean peak plasma concentra tion was 4 x 10~6 M. There was little drug accumulation on this schedule, as trough concentrations between p.o. doses often dropped below 1 x 10~6 M. The drug was metabolized extensively to a metabolite, the concentrations of which ex ceeded parent 13-c/s-retinoic acid concentrations with chronic dosing. Retinol concentrations were below the normal range.