Metabolites in safety testing

Traditionally, only circulating concentrations of parent drug have been measured in the rodent and nonrodent test species used for drug safety assessments and served as an index of systemic exposure for comparisons to human exposures. Circulating concentrations of metabolites have generally only been measured in specialized circumstances (e.g., parent compound was extensively metabolized). Measurement of only the parent compound is usually sufficient when the metabolite profile in humans is similar to that in at least one of the animal species used in the nonclinical safety assessment. However, it is possible that metabolites formed in humans might not be present in the rodent and nonrodent test species used for drug safety assessments or the metabolites are formed at disproportionately higher concentrations in humans than in the animal test species. Generally, metabolites identified only in human plasma or metabolites present at disproportionately higher concentrations in humans than in any of the animal...