Stephanie van Hoppe

149 The impact of OATPs on disposition and toxicity of antitumor drugs; insights from KO and humanized mice mouse livers, instead of both simultaneously as in humans. The substantial impact of either transporter alone therefore suggests an even stronger impact of OATP1Bs on doxorubicin pharmacokinetics in humans, especially affecting plasma clearance and hepatic uptake characteristics. Obviously, for a drug with a narrow therapeutic index like doxorubicin, this might be critical for its therapeutic efficacy and toxicity in patients. It may therefore also be of interest to investigate possible associations between OATP activity and doxorubicin pharmacokinetics, therapeutic efficacy, and toxicity in patient cohorts. 2 . 5 . P l a t i num c hemo t he r apeu t i c s Cisplatin and more recent platinum chemotherapeutics such as carboplatin and oxaliplatin are used to treat a wide spectrum of cancers, including testicular, bladder, lung, ovarian, colorectal, cervical, and breast cancers, as well as some lymphomas and sarcomas. In a COMPARE analysis of 60 human tumor cell lines (the well-characterized NCI-60 panel), Lancaster et al. (2013) found that high OATP1B3 expression as judged by Real-time RT-PCR was statistically significantly linked with sensitivity to the cytotoxicity of 9 anticancer drugs, amongst which cisplatin, carboplatin, and a platinum compound structurally related to oxaliplatin. UnlikeOATP1B1, whichwas found to be only expressed in liver and liver tumor tissue, OATP1B3 was found expressed in a range of different tissues and derived tumor tissue samples, suggesting that it might play a role in tumor sensitivity to platinum compounds. Subsequent in vitro studies revealed that humanOATP1B3 andOATP1B1 canmediate the cellular uptake of Pt upon exposure to cisplatin, and additionally OATP1B3 can mediate cellular Pt uptake upon exposure to carboplatin and oxaliplatin. In vivo studies with cisplatin administered intraperitoneally to wild-type and Oatp1b2-/- mice showed up to 35% reduced liver levels of Pt in the knockout mice shortly after administration, and 2.5-fold higher urinary excretion of Pt, the latter amounting to more than 60% of the administered dose (Lancaster et al., 2013). The data suggest a rapid and substantial liver uptake of a fraction of Pt being mediated by Oatp1b2 in wild-type mice. In the Oatp1b2-/- mice this Pt fraction may instead be excreted primarily into the urine. As a consequence, the plasma levels of Pt are not much different between the two strains. It should be noted, however, that cisplatin is highly reactive, for instance with carbonate, and the Oatp1b2-mediated Pt uptake may therefore well represent uptake of various resulting negatively charged Pt complexes instead of cisplatin itself. Cisplatin also binds irreversibly to plasma proteins, further complicating pharmacokinetic analyses. However that may be, in vivo Oatp1b2 function does clearly affect the pharmacokinetics of cisplatin-derived Pt. Extrapolating to human patients, this could mean that variations in OATP1B1 and OATP1B3 expression and activity in liver, in other tissues, and