Metabolites of all-trans-retinoic acid in bile: identification of all-trans- and 13-cis-retinoyl glucuronides.

The metabolites of all-trans-[3H]retinoic acid were studied in the rat bile. In the bile duct cannulated rat 80 to 86% of the dose is excreted into the bile within 24 h after the intravenous administration of either a physiological or pharmacological dose of all-trans-[3H]retinoic acid. Polar metabolites of retinoic acid predominate (73 to 96% of bile 3H) in the bile at all times; some free retinoic acid (0.2 to 4.8% of bile 3H) is excreted into the bile during the initial 6-h period after dosing. Retinoyl glucuronides are excreted into the bile for 12 h after dosing; their excretion is highest during the first 2 h. More retinoyl glucuronide is excreted from the pharmacological dose (10% of the radiolabel dose) than the physiological dose (4.4% of the dose) of all-trans-retinoic acid. The retinoyl glucuronides were separated and were shown to consist of all-trans- and 13-cis-retinoyl glucuronides in a ratio of 1.5 to 1.0. Since the starting material was 99% all-trans-retinoic acid and the methods used do not cause isomerization, it is concluded that cis-trans isomerization of retinoic acid is a physiologically relevant reaction.