Portal de Periódicos da CAPES

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

2005; American Society for Pharmacology and Experimental Therapeutics; Volume: 33; Issue: 10 Linguagem: Inglês

10.1124/dmd.105.005041

1521-009X

Dennis A. Smith, R. Scott Obach,

Computational Drug Discovery Methods

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"), 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.