Metabolic fate of [3H]-l-menthol in the rat.

[3-3H]-l-Menthol was administered by oral gavage to intact and bile duct-cannulated male Fischer 344 rats at a dose level of 500 mg/kg. Excreta were collected for up to 48 hr and metabolites in urine and bile analyzed by TLC, solid phase extraction, GLC, and GC/MS. In intact rats, some 71% of the dose was recovered in 48 hr with approximately equal amounts in urine and feces. Seventy-four percent of the dose was recovered from bile duct-cannulated rats, with 67% in the bile and 7% in the urine. The major biliary metabolite was menthol glucuronide, which undergoes enterohepatic circulation. The urinary metabolites resulted from hydroxylation at the C-7 methyl group at C-8 and C-9 in the isopropyl moiety, resulting in a series of mono- and dihydroxy-menthols and carboxylic acids, some of which are excreted in part as glucuronic acid conjugates. In addition, menthol glucuronide is found in the urine. The results have enabled the construction of a metabolic map for menthol in the rat that provides the basis for structure-metabolism relationships describing the fate of numerous menthol congeners of flavor importance.