| Identification of Novel Metabolites of Rosiglitazone in Freshly Isolated Human, Rat, and Monkey Hepatocytes by Liquid Chromatography/Tandem Mass Spectrometry |
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1 Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Shinagawa-ku, TOKYO, JAPAN 2 Daiichi Sankyo RD Associe Co., Ltd., Shinagawa-ku, TOKYO, JAPAN 3 Drug Metabolism Department, Daiichi Sankyo Europe GmbH, München, GERMANY |
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| The in vitro metabolism of rosiglitazone (RGZ) was studied in freshly isolated human, rat, and monkey hepatocytes. The metabolites of [14C]RGZ produced by incubation with hepatocytes were detected by radioactivity detection high-performance liquid chromatography. Seven metabolites (M1-M7) of RGZ were detected in human hepatocytes. The structures of the metabolites were elucidated by liquid chromatography/tandem mass spectrometry using electrospray ionization. The structural analysis demonstrated that M1, M2, and M4 were novel metabolites of RGZ. M1 was identified as a 2,4-thiazolidinedione (TZD) ring-opened N-glucuronide. M2 was identified as a TZD ring N-glucuronide. M4 was proposed to be a TZD ring-opened methylmercapto amide. Similarly, these metabolites were also detected in rat and monkey hepatocytes. To our knowledge, this is the first report on N-glucuronidation of TZD rings. Based on the structures of the metabolites, we propose the following novel in vitro metabolic pathways for RGZ: 1) N-glucuronidation of the TZD ring of RGZ to form M2 followed by hydrolysis to the TZD ring-opened N-glucuronide M1; and 2) methylation of the mercapto group of the TZD ring-opened mercapto amide to form M4. | ||
| Key words: Rosiglitazone, Thiazolidinedione ring, N-Glucuronidation, Freshly isolated hepatocytes, LC/MS/MS | ||
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