Overview of metabolite safety testing from an industry perspective.

Regulatory guidelines on MIST were initially established in 2005 and finalized in 2008 by the US FDA and this has led to much discussion and debate on how to apply these recommendations in today's resource-constrained pharmaceutical environment. There are four aspects of MIST that impact on the field of bioanalysis: definition of a disproportionate human metabolite, establishment of nonclinical (animal) safety coverage for important human metabolites, degree of rigor in validation of bioanalytical methods to quantify metabolites when synthetic standards are available, and semiquantitation of metabolites when synthetic standards are not available. In this manuscript, each of these points has been addressed from a pharmaceutical industry standpoint, including a perspective on the necessary convergence of the fields of metabolite safety testing and bioanalysis.