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SEEING THROUGH THE MIST: ABUNDANCE VERSUS PERCENTAGE. COMMENTARY ON METABOLITES IN SAFETY TESTING

SEEING THROUGH THE MIST: ABUNDANCE VERSUS PERCENTAGE. COMMENTARY ON METABOLITES IN SAFETY TESTING Abstract 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 “metabolites in safety testing” (“MIST”) 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 182:188–196, 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Drug Metabolism and Disposition Am. Soc for Pharma & Experimental Therapeutics

SEEING THROUGH THE MIST: ABUNDANCE VERSUS PERCENTAGE. COMMENTARY ON METABOLITES IN SAFETY TESTING

Drug Metabolism and Disposition , Volume 33 (10): 1409 – Oct 1, 2005

SEEING THROUGH THE MIST: ABUNDANCE VERSUS PERCENTAGE. COMMENTARY ON METABOLITES IN SAFETY TESTING

Drug Metabolism and Disposition , Volume 33 (10): 1409 – Oct 1, 2005

Abstract

Abstract 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 “metabolites in safety testing” (“MIST”) 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 182:188–196, 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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Publisher
Am. Soc for Pharma & Experimental Therapeutics
Copyright
Copyright © Drug Metabolism and Disposition
ISSN
0090-9556
eISSN
1521-009X
DOI
10.1124/dmd.105.005041
pmid
15985503
Publisher site
See Article on Publisher Site

Abstract

Abstract 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 “metabolites in safety testing” (“MIST”) 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 182:188–196, 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.

Journal

Drug Metabolism and DispositionAm. Soc for Pharma & Experimental Therapeutics

Published: Oct 1, 2005

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