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Drug Metabolism Letters


ISSN (Print): 1872-3128
ISSN (Online): 1874-0758

LC-MS/MS-Based Approach for Obtaining Exposure Estimates of Metabolites in Early Clinical Trials Using Radioactive Metabolites as Reference Standards

Author(s): Donglu Zhang, Nirmala Raghavan, Theodore Chando, Janice Gambardella, Yunlin Fu, Duxi Zhang, Steve E. Unger and W. Griffith Humphreys

Volume 1, Issue 4, 2007

Page: [293 - 298] Pages: 6

DOI: 10.2174/187231207783221411

Price: $65


An LC-MS/MS-based approach that employs authentic radioactive metabolites as reference standards was developed to estimate metabolite exposures in early drug development studies. This method is useful to estimate metabolite levels in studies done with non-radiolabeled compounds where metabolite standards are not available to allow standard LC-MS/MS assay development. A metabolite mixture obtained from an in vivo source treated with a radiolabeled compound was partially purified, quantified, and spiked into human plasma to provide metabolite standard curves. Metabolites were analyzed by LC-MS/MS using the specific mass transitions and an internal standard. The metabolite concentrations determined by this approach were found to be comparable to those determined by valid LC-MS/MS assays. This approach does not requires synthesis of authentic metabolites or the knowledge of exact structures of metabolites, and therefore should provide a useful method to obtain early estimates of circulating metabolites in early clinical or toxicological studies.

Keywords: LC-MS/MS, radiodetection, FIH, metabolite quantitation, metabolite profiling

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