Recent progress in in vivo phenotyping technologies for better prediction of transporter-mediated drug-drug interactions.

Clinical reports on transporter-mediated drug-drug interactions (TP-DDIs) have rapidly accumulated and regulatory guidance/guidelines recommend that sponsors consider performing quantitative prediction of TP-DDI risks in the process of drug development. In vitro experiments for characterizing the function of drug transporters have been established and various parameters such as the inhibition constant (Ki) of drugs and the intrinsic uptake/efflux clearance for a certain transporter can be obtained. However, many reports have indicated large discrepancies between the parameters estimated from in vitro experiments and those rationally explaining drug pharmacokinetics. Thus, it is essential to evaluate directly the function of each transporter isoform in vivo in humans. At present, several transporter substrate drugs and endogenous compounds have been recognized as probe substrates for a specific transporter and transporter function was evaluated by monitoring the plasma and urine concentration of those probes; however, few compounds specifically transported via a single transporter isoform have been found. For monitoring the intraorgan concentration of drugs, positron emission tomography can be a powerful tool and clinical examples for quantification of in vivo transporter function have been published. In this review, novel methodologies for in vivo phenotyping of transporter function are summarized.