Rationalization and prediction of in vivo metabolite exposures: the role of metabolite kinetics, clearance predictions and in vitro parameters

Importance of the field: Due to growing concerns over toxic or active metabolites, significant efforts have been focused on qualitative identification of potential in vivo metabolites from in vitro data. However, limited tools are available to quantitatively predict their human exposures. Areas covered in this review: Theory of clearance predictions and metabolite kinetics is reviewed together with supporting experimental data. In vitro and in vivo data of known circulating metabolites and their parent drugs were collected and the predictions of in vivo exposures of the metabolites were evaluated. What the reader will gain: The theory and data reviewed will be useful in early identification of human metabolites that will circulate at significant levels in vivo and help in designing in vivo studies that focus on characterization of metabolites. It will also assist in rationalization of metabolite-to-parent ratios used as markers of specific enzyme activity. Take home message: The relative importance of a metabolite in comparison to the parent compound as well as other metabolites in vivo can only be predicted using the metabolite's in vitro formation and elimination clearances, and the in vivo disposition of a metabolite can only be rationalized when the elimination pathways of that metabolite are known.