Isolation and identification of novel metabolites of gemfibrozil in rat urine

Gemfibrozil (GEM) is a clofibrate analog used to treat moderate to severe h ypertriglyceridemias. In lab animals, GEM causes peroxisome proliferation, an effect that has been associated with hepatocarcinogenesis in rats. In hu mans, hepatobiliary disorders, but not carcinogenesis, have been associated with GEM therapy. In the present study [C-14]GEM was administered orally t o rats at a dose of 2000 mg/kg. At various time points, radioactivity in ur ine was analyzed by liquid scintillation spectrometry, high-pressure liquid chromatography, liquid chromatography/mass spectrometry(n), gas chromatogr aphy/mass spectroscopy, and nuclear magnetic resonance. Nine metabolites of GEM were identified, some that have not been reported previously. Although the majority of metabolites were glucuronidated, some nonglucuronidated me tabolites were identified in urine, including a diol metabolite (both ring methyls hydroxylated), and the product of its further metabolism, the acid- alcohol derivative (ortho ring methyl hydroxylated, meta ring methyl comple tely oxidized to the acid). Hydroxylation of the aromatic ring also was a c ommon pathway for GEM metabolism, leading to the production of two phenolic metabolites, only one of which was detected in the urine in the nonconjuga ted or free form. Also of interest was the finding that both acyl and ether glucuronides were produced, including both glucuronide forms of the same m etabolite (e.g., 1-O-GlcUA, 5'-COOH-GEM, and 5'-COO-GlcUA-GEM); the positio ns and functionality of the glucuronide conjugates were identified using ba se hydrolysis or glucuronidase treatment, in combination with liquid chroma tography/MSn and nuclear magnetic resonance.