Stephanie van Hoppe

150 Chapter 6 especially in tumors, might affect the efficacy and toxic side effects of cisplatin-based chemotherapy. It will therefore be of interest to extend preclinical studies of cisplatin to OATP1B1- and OATP1B3-humanized Oatp1a/1b knockout strains, and also include studies of carboplatin and oxaliplatin. It will further be worthwhile to assess whether part of the high interindividual variation in efficacy and toxicity of these drugs seen in patients can in part be attributed to variations in OATP function. 2 . 6 . Ty r o s i ne k i na s e i nh i b i t o r s Tyrosine kinase inhibitors (TKIs), with as prime example imatinib (Gleevec), have to an extent revolutionized the treatment of a number of malignancies (Druker et al., 2001). As of 2015, more than 28TKIs have been FDA-approved (Wu et al., 2015). These rationally designed, targeted anticancer drugs canmake use of specific vulnerabilities of the tumor cells, for instance by targeting specific oncogenic mutations in proteins, thus increasing disease-specificity and reducing the risk of toxic side effects. Understandably, there has been significant interest in whether TKIs are transported OATP substrates, as this could affect their accumulation in tumor cells as well as in various important tissues in the body, and control their plasma pharmacokinetics and elimination. Such parameters can be decisive in the overall therapeutic efficacy and tolerability of anticancer and other drugs. While many TKIs have now been tested for interaction with OATPs, the in vivo relevance for transport of the unchanged parent compounds appears to be quite limited. In RNA-injected Xenopus oocytes, human OATP1A2 mediates modest imatinib uptake, OATP1B3 a little, and OATP1B1 none (Hu et al., 2008). Initial tests failed to show significant uptake of sorafenib and sunitinib mediated by OATP1A2, OATP1B1, and OATP1B3 in RNA-injected Xenopus laevis oocytes (Hu et al., 2008). However, later tests in highly OATP-overexpressing HEK293 cells reported significant uptake transport of crizotinib, nilotinib, pazopanib, and sorafenib by OATP1B1 and OATP1B3; of imatinib, gefitinib, dasatinib, vandetanib, and vemurafenib by OATP1B3 but not by OATP1B1; and of sunitinib by OATP1B1 but not OATP1B3 (Zimmerman et al., 2013). It should be noted, however, that often OATP-mediated relative levels of uptake of TKIs in the various in vitro model systems were small compared to those of the anionic OATP control substrates. Modern targeted TKIs are rarely, if at all, designed to be anionic, given the usual requirements of good oral availability (intestinal absorption) and efficient tumor cell penetration of these compounds. A possible further cause of discrepancies between in vitro and in vivo OATP-mediated transport results for certain drugs is discussed later in this review (section 4).