Chapter 2: Drug Transporters in the Liver: Their Involvement in the Uptake and Export of Endo- and Xeno-biotics

The liver is a key organ in the metabolism and elimination of drugs. Since drug metabolism is located within hepatocytes, drugs destined for metabolism need to enter hepatocytes and the metabolites formed subsequently need to leave the hepatocytes again. Both uptake of drugs and exit of metabolites (or in some instances unchanged drug) are mediated by transport proteins. This chapter describes key transporters mediating this uptake into and export from hepatocytes. Hepatocytes constitute the majority of cells in the liver and are strategically located between blood and bile. The sinusoidal (also called basolateral) membrane of hepatocytes faces the blood plasma and the canalicular (also called apical) membrane of hepatocytes faces the bile. The pattern of transporters expressed in the two domains differs, hence making hepatocytes polar cells. The basolateral membrane contains members of the solute carrier (SLC) gene families SLCO and SLC22. Specific transporters of these families are organic anion transporting polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter (OCT) 1, OCT3, organic anion transporter (OAT) 2 and OAT7. These transporters mediate the uptake of a large number of drugs, including some widely used ones such as statins and metformin. In addition, the basolateral membrane expresses the ATP binding cassette (ABC) proteins multidrup resistance associated protein (MRP) 3 and MRP4, which efflux drug metabolites back into the blood plasma for renal elimination. At the canalicular membrane, drugs or their metabolites are eliminated into bile, while drug uptake is not an issue. This is accomplished by ABCG2, MRP2 and multidrug resistance protein (MDR) 1. In addition to drug metabolism and elimination, the liver produces bile, of which bile salts are major constituents. Uptake of bile salts into hepatocytes is mediated by Na⁺/taurocholate cotransporting polypeptide (NTCP), and to a minor extent by OATPs, while secretion of bile salts across the canalicular membrane is achieved by bile salt export pump (BSEP). Both of these mainly bile salt transport systems have been demonstrated in vitro to be capable of drug transport, but their contribution to drug elimination in vivo is currently not known. The regulatory agencies require or recommend that, during drug development, selected transporters, due to their pivotal role in drug disposition, are tested for their involvement in drug disposition and in pharmacokinetic drug–drug interactions. Finally, software tools that have been developed to model drug disposition and kinetic parameters of drugs for specific transport systems are being incorporated into these software tools. They are becoming increasingly important to model potential drug–drug interactions in humans and help to decide whether drug–drug interaction studies should be performed in humans.