Stephanie van Hoppe

132 Chapter 6 single mouse representative of the mammalian OATP1B subfamily ( Figure 1 ), might be more or less equivalent to the deficiency of OATP1B1 and OATP1B3 in humans (e.g., Zaher et al., 2008). However, for many OATP substrates this assumption clearly does not apply. In humans, OATP1B1 and OATP1B3 are the only members of the OATP1A/1B family that are present in the basolateral membrane of liver parenchyme cells, and thus involved in the uptake of substrates from blood into the liver. Human OATP1A2 is also expressed in the liver, but only found in the cholangiocytes, and therefore irrelevant for the direct uptake of compounds fromblood into the liver. In contrast, in themouse there are two OATP1A proteins that are substantially present in the sinusoidal membrane of liver parenchyme cells, Oatp1a1 and Oatp1a4. This means that for any substrate that is substantially transported by both Oatp1b2 and either or both of Oatp1a1 or Oatp1a4, results obtained in single Oatp1b2-/- mice may underestimate the effects of OATP1B1 and OATP1B3 deficiency in humans. A case in point is the role of OATP1B1 and OATP1B3 in the uptake of conjugated bilirubin. Whereas single Oatp1b2(-/-) mice showed only a marginal increase in plasma total and conjugated bilirubin levels (Lu et al., 2008; Zaher et al., 2008), in full Oatp1a/1b(-/-) mice there was a pronounced increase in plasma bilirubin glucuronide levels (van de Steeg et al., 2010). The latter observation pointed to the prominent role that human OATP1B1 and OATP1B3 play in the reuptake of conjugated bilirubin in human liver, and provided the mechanistic explanation for the human Rotor syndrome caused by full OATP1B1 and OATP1B3 deficiency (van de Steeg et al., 2012). Clearly, the redundant role of Oatp1a1 and Oatp1a4 relative to Oatp1b2 in hepatic uptake of conjugated bilirubin in the mouse obscured the important contribution of the human OATP1B proteins in this process. Great care must therefore be taken when extrapolating from results in Oatp1b2(-/-) mice to the functional role of the human OATP1B1 and OATP1B3 proteins in liver. For pharmacokinetic studies, given the very substantial but incomplete and unpredictable overlap in substrate specificity between the various mouse and human OATP1A/1B transporters, every drug should be carefully assessed in its own right, and great caution should be used in extrapolating from results obtained in single knockout strains to the human situation. Keeping these caveats in mind, in this review we will focus on recent studies performed with these mouse models for a range of anticancer drugs. Figure 2 provides an overview of the structures of these drugs, also illustrating their structural diversity. The aim of such studies was to obtain basic insight into the handling of the anticancer drugs by OATP1A/1B proteins, in the hope that this knowledge may ultimately be used to improve current anticancer drug treatment regimens, by enhancing therapeutic efficacy of these drugs, reducing toxic side effects, and possibly both.