Stephanie van Hoppe

153 The impact of OATPs on disposition and toxicity of antitumor drugs; insights from KO and humanized mice 3 . 1 . Hepa t o c y t e hopp i ng o f b i l i r ub i n g l u c u r on i de This process inferred to explain the behavior of sorafenib glucuronide was highly reminiscent of the previously proposed “hepatocyte hopping” process for the endogenousmetabolitebilirubinglucuronide (Iusuf et al., 2012c; vandeSteeget al., 2012; van de Steeg et al., 2010). The hydrophobic, very poorly water-soluble, and potentially highly toxic unconjugated bilirubin, the primary breakdown product of heme (from hemoglobin) degradation, is directly transported from the spleen, where red blood cells are mostly degraded, via the splenic and portal veins, to the liver. Extensive binding to plasma albumin prevents precipitation of bilirubin in blood. Bilirubin is then efficiently taken up into the liver, presumably in part by Oatp1a/1b transporters, but also by one or more other, substantial, transport mechanisms, which may or may not include passive diffusion. Inside the hepatocytes bilirubin is efficiently conjugated by UGT1A1 to yield bilirubin glucuronide, which is more water-soluble and generally easier to detoxify by the body. Normally, the bulk of hepatic bilirubin glucuronide is excreted into the bile by the ABCC2multidrug efflux transporter and then released into the small intestinal lumen to leave the body through the feces. However, analysis with a range of different single and combination transporter knockout and transgenic mouse strains has revealed that also under normal circumstances a substantial fraction of hepatic bilirubin glucuronide (possibly up to half of the total amount formed) is secreted by the multidrug efflux transporter ABCC3 across the basolateral (sinusoidal) membrane of hepatocytes into the blood (van de Steeg et al., 2013; van de Steeg et al., 2010). Most of this bilirubin glucuronide is quickly taken up again into the liver by Oatp1a/1b proteins in the mouse, and by OATP1B1 and OATP1B3 in humans, a cycle resulting in very low overall plasma levels of conjugated bilirubin in the general circulation. In contrast, in mice that lack Oatp1a/1b proteins, or in humans that lack both OATP1B1 and OATP1B3 in the liver, the interruption of this cycle leads to highly increased plasma levels of conjugated bilirubin in the general circulation, and somewhat increased levels of unconjugated bilirubin, causing a disorder known as Rotor syndrome (van de Steeg et al., 2012). The phenotype of this Rotor-type conjugated hyperbilirubinemia is fortunately quite benign, mainly a generally mild jaundice. The underlying mechanistic process, where bilirubin glucuronide is secreted from a hepatocytebyABCC3intothesinusoidalblood,onlytobetakenupagaininadownstream hepatocyte via Oatp1a/1b or OATP1B proteins, has been called “hepatocyte hopping”, as it allows bilirubin glucuronide to readily “hop” from one hepatocyte to the next. It has been speculated that this hepatocyte hopping process might be beneficial under circumstances where the bile canalicular excretion of bilirubin glucuronide through ABCC2 in upstream situated hepatocytes is overloaded or otherwise compromised. The hepatocyte hopping salvage pathway for such trapped bilirubin glucuronide allows it