Quantitative assessment of the risk of OATP1B1/1B3-mediated drug-drug interactions

Abstract

Drug transporters play important roles in determining drug pharmacokinetics. Organic anion transporting polypeptides 1B1/1B3 (OATP1B1/1B3) are transporters mediating hepatic uptake of various anionic drugs. OATP1B1/1B3 activities are changed by genetic mutation and drug-drug interaction (DDI) that could lead to severe adverse reactions. Methods to address the precise DDI risk assessment have been developed in addition to the translational assessment from the results of in vitro studies. Using endogenous substrates as probes is an emerging approach that allows clinical assessment of the DDI risk in the early phase of drug development. Then, the clinical data will be subjected to the pharmacokinetic analysis using physiologically-based pharmacokinetic models to perform the more realistic DDI risk assessment with OATP1B1/1B3 substrate drugs. When drug targets are located inside the hepatocytes, DDI impact on the intrahepatic concentration is critical for their pharmacological actions. Positron emission tomography (PET) allows researchers to determine tissue concentration time profiles of the PET probe upon the inhibition of OATP1B1/1B3, and to estimate the change in kinetic parameter for each intrinsic process of hepatic elimination of PET probe. Integration of the clinical data into the PBPK model realizes more precise prediction of DDI impact on the pharmacokinetics of drugs, and their therapeutic effects.