Abstract
Liquid chromatography–ion trap mass spectrometry was used for the detection and structural characterization of metabolites of the anti-obesity drug sibutramine. Metabolites were profiled from incubations of sibutramine in primary cultures of rat hepatocytes. In addition, enantioselectivity of sibutramine metabolism was investigated by carrying out separate incubations with (R)- and (S)-sibutramine. As a result, biotransformation profile for sibutramine with rat hepatocytes is proposed. Nineteen metabolites and several of their isomers formed via demethylation, hydroxylation, dehydrogenation, acetylation, attachment of CO2, and glucuronidation were identified in MS2 and MS3 experiments, though the exact position of the functionality, mostly hydroxylation, could not always be determined from the mass spectrometric information. However, clear enantioselective formation was observed for two hydroxyl derivatives and two glucuronide conjugates, indicating that the hydroxyl/glucuronic acid moiety in those structures is close to the chiral center. Most of the metabolites found in this study are new metabolites of sibutramine, which were not previously reported.
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Acknowledgement
This work was supported by the Finnish Funding Agency for Technology and Innovation, Orion Pharma, Juvantia Pharma, Zeptos, Danisco Sugar and Sweeteners, and United Laboratories.
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Hakala, K.S., Link, M., Szotakova, B. et al. Characterization of metabolites of sibutramine in primary cultures of rat hepatocytes by liquid chromatography–ion trap mass spectrometry. Anal Bioanal Chem 393, 1327–1336 (2009). https://doi.org/10.1007/s00216-008-2540-8
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DOI: https://doi.org/10.1007/s00216-008-2540-8