SEEING THROUGH THE MIST: ABUNDANCE VERSUS PERCENTAGE. COMMENTARY ON METABOLITES IN SAFETY TESTING
Recent attention has been given to the potential roles that metabolites could play in safety evaluations of new drugs. In 2002, a proposal was published on âmetabolites in safety testingâ (âMISTâ) [T. A. Baillie, M. N. Cayen, H. Fouda, R. J. Gerson, J. D. Green, S. J. Grossman, L. J. Klunk,...
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Published in | Drug metabolism and disposition Vol. 33; no. 10; pp. 1409 - 1417 |
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Main Authors | , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.10.2005
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Subjects | |
Online Access | Get full text |
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Summary: | Recent attention has been given to the potential roles that metabolites could play in safety evaluations of new drugs. In
2002, a proposal was published on âmetabolites in safety testingâ (âMISTâ) [T. A. Baillie, M. N. Cayen, H. Fouda, R. J. Gerson,
J. D. Green, S. J. Grossman, L. J. Klunk, B. LeBlanc, D. G. Perkins, and L. A. Shipley (2002) Toxicol Appl Pharmacol 182:188â196], which suggested some guidelines regarding when it is necessary to provide greater assessment of the safety
of metabolites. However, this proposal was based on relative abundance values, i.e., the percentage that a metabolite comprises
of total exposure to drug-related material. In the present commentary, we propose that absolute abundance criteria be used
rather than relative abundance. The absolute abundance of a metabolite in circulation or excreta in humans should be combined
with other information regarding the chemical structure of the metabolite (e.g., similarity to the parent drug, presence of
chemically reactive substituents) and potential mechanisms of toxicity (e.g., suprapharmacological effects, secondary pharmacological
effects, nonspecific effects). Decision trees are described that can be used to address human metabolites in safety testing. |
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ISSN: | 0090-9556 1521-009X |
DOI: | 10.1124/dmd.105.005041 |