Stephanie van Hoppe

157 The impact of OATPs on disposition and toxicity of antitumor drugs; insights from KO and humanized mice of drugs and other compounds will be affected by the hepatocyte hopping process to a greater or lesser extent. Moreover, additional broad-specificity canalicular and sinusoidal transporters in the liver, such as ABCG2, possibly ABCB11, ABCC4, and OATP2B1, are likely to further contribute to a wide-ranging impact of the hepatocyte hopping process. 4 . S p e c i f i c i t y o f OAT P1A / 1B - me d i at e d drug t r an s p o r t may d e p e nd on t h e c e l lu l a r con t e x t In the context of this review it is worth noting that in some cases, for unknown reasons, it appears that transport of OATP substrates is strongly dependent on the cellular context (cell type) in which a specific OATP is expressed. For instance, de Graan et al. (2012) found that docetaxel was not appreciably taken up when OATP1B1 was expressed in Xenopus oocytes, whereas OATP1B3 in the same system readily mediated docetaxel uptake. In contrast, when OATP1B1 and OATP1B3 were expressed in a human embryonic kidney cell line (HEK293), or in a Chinese Hamster Ovary cell line (CHO), both transporters mediated more or less the same amount of docetaxel uptake. Very similar findings were reported for paclitaxel, which was readily transported by OATP1B1 and OATP1B3 expressed in HEK293 and CHO cells, but not by OATP1B1 expressed in Xenopus oocytes, whereas Xenopus -expressed OATP1B3 was active (Nieuweboer et al., 2014). Positive control substrates were readily taken up in all these cases. As described above, subsequent studies in humanized mice indicated that OATP1B1 and OATP1B3 can both transport docetaxel in vivo when expressed in mouse hepatocytes (Iusuf et al., 2015). Similar observations were further made for doxorubicin by Durmus et al. (2014), who found that in vitro in various OATP-transfected HEK293 cells, doxorubin was not appreciably taken up by human OATP1B1 or OATP1B3, whereas it was taken up by OATP1A2. In contrast, in transgenic humanized mice with overexpression of OATP1B1 or OATP1B3 in the liver, clearly increased liver-to-plasma ratios of doxorubicin were seen, indicating that in mouse hepatocytes these proteins can mediate appreciable doxorubicin uptake. Of note, though, transgenic OATP1A2 was even more effective in mediating doxorubicin uptake into mouse hepatocytes in vivo (Durmus et al., 2014). We therefore cannot exclude that the discrepancy with doxorubicin uptake in the cell lines may in part have been a sensitivity issue related to expression levels of the transporters. However that may be, the mechanistic background of such discrepancies is as yet a mystery. One can speculate that perhaps in some cases a covalent modification of an OATP (like phosphorylation or similar process) must occur in order for a certain substrate to be recognized, and that the capacity to make such modifications differs