Stephanie van Hoppe

143 The impact of OATPs on disposition and toxicity of antitumor drugs; insights from KO and humanized mice but similar to those in wild-type mice ( Figure 3C and D ). In theory this could either be caused by the up- and down-regulation of Ces1c, or by changes in SN-38 clearance. Interestingly, the liver levels in all tested strains were the same, and the liver-to-plasma ratios of SN-38 were identical between the wild-type and transgenic strains, but markedly higher than in Oatp1a/1b(-/-) mice. The latter result strongly suggests that the liver uptake of SN-38 was compromised in the Oatp1a/1b(-/-) mice, and mostly restored by OATP1B1 and OATP1B3 in the humanized strains ( Figure 3C and D ). 2 . 2 . 3 . SN - 38 d i s po s i t i on i n Oa t p1a / 1b ( - / - ) mi ce In an alternative approach to circumvent the complications of Ces upregulation in the Oatp1a/1b(-/-) mice, SN-38 was directly administered i.v. to these mice, at 1 mg/kg in view of the considerable solubility and formulation limitations of SN-38. This resulted in significantly higher plasma levels of SN-38 shortly after administration, and significantly lower liver concentrations compared to levels in wild-type mice. A reduced short-term liver uptake of SN-38 was further supported by a two-fold decrease in biliary excretion of SN-38 in the Oatp1a/1b(-/-) mice (Iusuf et al., 2014). Collectively, the mouse studies indicate that both irinotecan and SN-38 are cleared from plasma by uptake into the liver through one or more of the mouse hepatic Oatp1a/1b transporters. In contrast, the transgenic human OATP1B1 and OATP1B3 can mediate substantial liver uptake and plasma clearance of SN-38, but not of irinotecan. These results fit well with in vitro studies, which found that SN-38 is readily transported by human OATP1B and OATP1B3, whereas irinotecan is not (Nozawa et al., 2005; Oostendorp et al., 2009; Yamaguchi et al., 2008). The results indicate species differences in substrate specificity between the mouse and human hepatic OATP1A/1B proteins, as expressed in vivo inmouse hepatocytes. The irinotecan/SN-38 toxicity data in themouse strains are more difficult to interpret in view of the altered Ces1c levels and rate of SN-38 formation in Oatp1a/1b(-/-) mice. However, extrapolating from the delayed hepatic SN- 38 clearance in Oatp1a/1b(-/-) mice and its reversal by human OATP1B1 and OATP1B3, it seems very likely that also in humans these proteins are involved in the detoxification of SN-38. This would be in line with the clinical observations that partial deficiencies in OATP1B1 due to genetic polymorphisms correlate with increased irinotecan/SN-38 toxicity (Han et al., 2008; Takane et al., 2009; Xiang et al., 2006). The data of Iusuf et al. (2014) strongly suggest that this has primarily to do with delayed SN-38 clearance in these patients due to the compromised function of OATP1B1. 2 . 3 . Me t ho t r ex a t e Methotrexate is a folate antimetabolite that is used in the treatment of several important cancer types (breast cancer, lung cancer, head- and neck cancer, non-