METABOLISM OF ORAL 9-CIS RETINOIC ACID IN THE HUMAN - IDENTIFICATION OF 9-CIS-RETINOYL-BETA-GLUCURONIDE AND 9-CIS-4-OXO-RETINOYL-BETA-GLUCURONIDE AS URINARY METABOLITES

Data from a number of investigators suggest that the g-cis-isomer of R A(1) (9-cis-RA) may be a promising agent in chemoprevention and treatm ent of certain types of cancer. Therefore, clinical studies on this re tinoid have been initiated. However, up to now, no information has bee n published on the metabolism of 9-cis-RA in the human. Herein, we rep ort the first data on retinoid metabolism after multiple administratio n of 9-cis-RA (20 mg/day po) to human volunteers. After 2 and 12-13 hr , plasma concentrations of 9-cis-RA and its metabolites 9,13-dicis-RA, 13-cis-RA, and all-trans-RA were low. In contrast, dosing with 13-cis -RA yielded much higher plasma retinoid levels. Effects on plasma reti nol concentrations did not become obvious after any drug treatment. Se veral retinoid metabolites were found in the urine of 9-cis-RA-treated individuals, and 9-cis-RAG, as well as 9-cis-4-oxo-RAG, could be iden tified. After treatment with 9-cis-RA, high concentrations of the admi nistered drug were found in the feces, along with comparably low conce ntrations of 13-cis-RA, 9,13-dicis-RA, and all-trans-RA. Our report in dicates that 9-cis-RA is either eliminated much more rapidly than 13-c is-RA, or it is poorly absorbed, and presents the characterization of two urinary glucuronides.