Stephanie van Hoppe

156 Chapter 6 Figure 4 - Schematic diagram of hepatocyte hopping of sorafenib glucuronide and possible recirculationofsorafenib.Thisschematicpresentsthelikelysituationinhumanliver,asextrapolated from findings in various knockout and humanized mouse strains. After oral administration and intestinal absorption, sorafenib is taken up into the hepatocytes by incompletely defined mechanisms, possibly including OATP1B-type carriers, OCT1, passive diffusion, and perhaps other transporters. Within the hepatocytes, sorafenib undergoes conjugation by UGT1A9 to form sorafenib glucuronide (SG). SG is secreted into the bile primarily by ABCC2, but under physiological conditions a substantial fraction of intracellular SG can also be secreted back into the blood by sinusoidal ABCC3 and one or more other sinusoidal transport mechanisms. From there SG can be efficiently taken up again by downstream hepatocytes via OATP1B-type carriers (Oatp1a and Oatp1b carriers in mice), resulting in only low SG concentrations reaching the general circulation. This secretion-and-reuptake loop may help to prevent the saturation of ABCC2-mediated biliary SG secretion in hepatocytes positioned upstream within liver lobules. Overall, this can result in efficient biliary elimination and hepatocyte detoxification. Once secreted into the bile, SG enters the intestinal lumen where it can serve as a substrate for bacterial β-glucuronidases that regenerate sorafenib. This sorafenib can then undergo intestinal absorption, thus reentering the circulation. It has been proposed that this ongoing reabsorption of recirculated SG after hydrolysis to sorafenib contributes to the long-lasting sorafenib plasma levels observed in patients (Hilger et al., 2009; Jain et al., 2011; Vasilyeva et al., 2015). This figure was produced using Servier Medical Art (www.servier.com ).