A Novel Approach to Predicting Organic Anion Transporting Polypeptide Function in Human Hepatic Drug Disposition and Biliary Clearance

The transport of drugs into and out of the liver plays a critical role in determining drug disposition and therapeutic ef fi cacy. Competition between drugs or inhibition of transporter function also makes membrane transporters an important site for drug-drug-interactions that can impact therapeutic ef fi cacy and the likelihood of adverse effects. Among the numerous plasma membrane carrier proteins found in the liver, the organic anion transporting polypeptide (OATP; SLCO gene family) transporters are among the most important for many anionic drugs and amphiphilic substrates, including cancer chemotherapeutic agents (Kalliokoski and Niemi, 2009; Tu et al., 2013; van de Steeg et al., 2013). The OATP or SLCO gene family of transporters comprises 11 individual carrier proteins in humans (https://www.guidetopharmacology.org/ GRAC/FamilyDisplayForward?familyId=238). These carriers are further divided into 6 families and 10 sub-families based on amino acid sequence. While they all have in common the properties of 12 transmembrane domains with intracellular termini, multiple glycosylation sites, and the mediation of sodium-independent uptake of various amphiphilic substrates, the different carriers have distinct tissue localizations. There are six OATP proteins that are expressed in the liver, including SLCO1A2, SLCO2A1, and SLCO2B1 (ubiquitously expressed), SLCO1B1 and SLCO1B3 (selectively expressed in the liver), and SLCO4A1 (expressed in the liver as well as the heart, placenta, and lung). The importance of hepatic OATP transporters in drug design and development is highlighted by the recommendations from the U.S. Food and Drug Administration (Food and Drug Administration Center for Drug Evaluation and Research, 2020), European Medicines Agency (European Medicines Agency Committee for Human Medicinal Products, 2012), and Japan Ministry of Health, Labor and Welfare (Ministry of Health, Labour and Welfare Pharmaceuticals and Medical Device Agency,