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Fractional mass filtering as a means to assess circulating metabolites in early human clinical studies
Author(s) -
Tiller Philip R.,
Yu Sean,
Bateman Kevin P.,
CastroPerez Jose,
Mcintosh Ian S.,
Kuo Yushin,
Baillie Thomas A.
Publication year - 2008
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/rcm.3758
Subject(s) - chemistry , drug , human plasma , biotransformation , pharmacology , tandem mass spectrometry , metabolite , liquid chromatography–mass spectrometry , chromatography , drug development , mass spectrometry , computational biology , biochemical engineering , biochemistry , medicine , engineering , biology , enzyme
Recent changes in the regulatory environment have led to a need for new methods to assess circulating human drug metabolites in early clinical studies with respect to their potential toxicological impact. The specific goals of such studies are to determine if the metabolites present in human plasma following administration of a drug candidate also are observed in plasma from the animal studies employed for preclinical toxicological evaluation, and to estimate corresponding exposure margins (animal:human) for the major metabolites. Until recently, the accepted best practice for the characterization of circulating drug metabolites utilized liquid chromatography/tandem mass spectrometry (LC/MS/MS)‐based methodologies, in conjunction with authentic chemical standards, for the detection and quantitative analyses of metabolites predicted from both animal studies and experiments with human liver preparations in vitro . While this approach is satisfactory for anticipated biotransformation products, metabolites that were not expected to circulate in human plasma frequently escape detection. Current accurate mass instruments enable the use of the technique of fractional mass filtering to detect both expected and unexpected metabolites in a rapid, less resource‐intensive and more robust manner. Application of this technology to several clinical development programs at Merck Research Laboratories has demonstrated the value of fractional mass filtering in the assessment of circulating drug metabolites in early clinical trials. Copyright © 2008 John Wiley & Sons, Ltd.