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

0090-9556/05/3310-1409-1417$20.00
DMD 33:1409-1417, 2005

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COMMENTARY

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

Dennis A. Smith, and R. Scott Obach

Pharmacokinetics, Dynamics, and Metabolism, Pfizer, Inc., Sandwich, Kent, United Kingdom (D.A.S.) and Groton, Connecticut (R.S.O.)

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.

Address correspondence to: Dennis A. Smith, Pharmacokinetics, Dynamics, and Metabolism, Pfizer, Inc., Sandwich, Kent, UK CT13 9NJ. E-mail: dennis.a.smith{at}pfizer.com




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