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Drug Metabolism and Disposition Fast Forward
First published on June 28, 2005; DOI: 10.1124/dmd.105.005041

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Received for publication April 12, 2005.
Revised June 17, 2005.
Accepted for publication June 24, 2005.

Seeing Through the MIST: Abundance Versus Percentage. Commentary on Metabolites in Safety Testing

Dennis A. Smith 1* R Scott Obach 1

1 Pfizer, Inc.

* Address correspondence to: E-mail: dennis.a.smith{at}pfizer.com

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") (Baillie, et al., (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, non-specific effects). Decision trees are described that can be used to address human metabolites in safety testing.


Key words: drug development, drug toxicity, toxicology


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