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

Abstract

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.

Figure 1. Relationship between the single dose and steady-state in vivo AUC_m/AUC_p for 25 M/P pairs

The solid line indicates no difference and the dashed line indicates a 2-fold difference between single dose and steady-state dosage regimens.

Figure 2. Schematic representation of the metabolic fate of a parent drug after PO or IV administration

In this scheme, D_g, D_h and D_s are the amounts of drug in the gut lumen, liver during first pass and systemic circulation, respectively. F_a and F_h are the fractions of drug that are absorbed into the enterocytes and that escape first pass elimination in the liver, respectively. The f_m,h term is the fraction of hepatic metabolism that results in the metabolite of interest and M_h and M_s refer to the amount of metabolite of interest, formed from first pass in the liver and systemic elimination, respectively.