Pharmacokinetics of 13-Cis-Retinoic Acid in Patients with Advanced Cancer

13-cis-Retinoic acid (13-CRA) is a synthetic analog of vitamin A effective in reversing preneoplastic lesions in both humans and animals. To study its physicochemical properties and disposition kinetics, we developed a rapid, sensitive, and precise high-performance liquid chromatography assay for 13-CRA in biological samples. This assay system resulted in a clear separation of 13-CRA from all-trans-retinoic acid and retinol and had a detection limit of 20 ng/ml plasma. Recovery was 89 ± 6% (S.D.) at equivalent physiological concentrations with a precision of 8%. To study the disposition kinetics in humans, 13 patients received a p.o. bolus of 13-CRA and had blood samples collected at timed intervals. For the 10 patients studied on the first day of 13-CRA administration, the mean time to peak plasma concentration was 222 ± 102 min. Inter-patient peak 13-CRA plasma concentrations were found to be variable, suggesting irregular gastrointestinal absorption. ß-Phase t_1/2 was approximately 25 hr. The prolonged terminal-phase plasma half-life may represent biliary excretion and enterohepatic circulation.