Abstract
After oral administration of 14C-labeled gemfibrozil to male dogs, ten metabolites of gemfibrozil, designated as dog metabolite (DM)-1, DM-2, DM-3, DM-4, DM-5-1, DM-5-2, DM-6, DM-7, DM-8, and DM-9, were detected in the urine. Structural analysis of these metabolites by mass spectrometry and tandem mass spectrometry in various ionization modes demonstrated that DM-1, DM-2, DM-3, DM-4, DM-5-1, DM-5-2, and DM-6 were previously unreported metabolites of gemfibrozil. With the exception of DM-8 and DM-9, the gemfibrozil metabolites in dog urine were conjugated metabolites produced by glucuronidation at the carboxylic acid group and the phenolic hydroxyl group generated metabolically or by sulfo-conjugation at the phenolic hydroxyl group. Interestingly, DM-1 and DM-2 were demonstrated to be unique, doubly conjugated forms of DM-9. In DM-1, glucuronidation had occurred at both the carboxylic acid group and phenolic hydroxyl group. In DM-2, sulfo-conjugation at the phenolic hydroxyl group and glucuronidation at the carboxylic acid group had occurred. Therefore, the dogs were found to possess enzymatic mechanisms that glucuronidate or sulfo-conjugate already conjugated metabolites, converting water-soluble metabolites to hydrophilic metabolites.
