Biomarkers for In Vivo Assessment of Transporter Function

Drug-drug interactions are a major concern not only during clinical practice, but also in drug development. Due to limitations of in vitro-in vivo predictions of transporter-mediated drug-drug interactions, multiple clinical Phase I drug-drug interaction studies may become necessary for a new molecular entity to assess potential drug interaction liabilities. This is a resource-intensive process and exposes study participants, who frequently are healthy volunteers without benefit from study treatment, to the potential risks of a new drug in development. Therefore, there is currently a major interest in new approaches for better prediction of transporter-mediated drug-drug interactions. In particular, researchers in the field attempt to identify endogenous compounds as biomarkers for transporter function, such as hexadecanedioate, tetradecanedioate, coproporphyrins I and III, or glycochenodeoxycholate sulfate for hepatic uptake via organic anion transporting polypeptide 1B or N¹-methylnicotinamide for multidrug and toxin extrusion protein-mediated renal secretion. We summarize in this review the currently proposed biomarkers and potential limitations of the substances identified to date. Moreover, we suggest criteria based on current experiences, which may be used to assess the suitability of a biomarker for transporter function. Finally, further alternatives and supplemental approaches to classic drug-drug interaction studies are discussed.