Stephanie van Hoppe

127 The impact of OATPs on disposition and toxicity of antitumor drugs; insights from KO and humanized mice 1 . I n t r odu c t i on to OAT P1A / 1B t r an s p o r t e r s and g e n e t i c a l ly mod i f i e d mou s e mod e l s to s t ud y t h e i r f un c t i on s 1 . 1 . P r ope r t i e s o f OATP1A / 1B t r an s po r t e r s Organic anion-transporting polypeptide (OATP) uptake transporters can play a major role in the uptake of numerous compounds, including many anticancer drugs, into cells and organs. Positioned in the plasma membrane, these multispanning transmembrane proteins can mediate the uptake of a structurally highly diverse range of substrates into the cell, by as yet incompletely resolved mechanisms. As a consequence, they can have a major impact on the pharmacokinetic disposition of transported drugs, determining their oral availability and plasma clearance, as well as their distribution to liver and other organs, and the main route(s) of elimination (for recent reviews see: Gong and Kim, 2013; Konig et al., 2013; Niemi et al., 2011; Shitara et al., 2013; Stieger and Hagenbuch, 2014). OATPs can therefore have a strong effect on the therapeutic efficacy, but also the toxic side effects of substrate drugs. Moreover, several OATPs are variably expressed in a range of human cancers. As this may obviously influence the effective intracellular exposure of the cancer cells to OATP substrate anticancer drugs, this can directly affect the therapy susceptibility of these cancers (for recent reviews see: Nakanishi and Tamai, 2014; Obaidat et al., 2012; Sissung et al., 2012; Thakkar et al., 2015). The activity of the human OATPs that are thought to be most important for the general pharmacokinetic behavior of drugs, OATP1A2, OATP1B1, and OATP1B3 (as well as possibly OATP2B1, but see below), can further vary dramatically because of genetic polymorphisms and mutations that affect drug transport, but also because of drug-drug interactions with a variety of coadministered drugs (e.g. Durmus et al., 2015; Franke et al., 2009; Gong and Kim, 2013; Konig et al., 2013; Niemi et al., 2011; Obaidat et al., 2012; Shitara et al., 2013; Stieger and Hagenbuch, 2014; van de Steeg et al., 2012). Given their obvious medical importance, it is crucial to obtain clear insight into the in vivo pharmacological, toxicological, and physiological functions of the OATP proteins, especially those of the OATP1A/1B family. One way to achieve this goal is to generate and study mouse strains that have the mouse Oatp1a and Oatp1b genes knocked out, or that have replaced the mouse Oatp1a/1b genes with one or more of their human analogues (although the formal gene name for the OATP-encoding genes is SLCO (for Solute Carrier of Organic Anions), for simplicity we will mostly use the OATP/Oatp nomenclature in this review). These mouse models can then be used to investigate the impact of the genetic modifications on the behavior of, amongst others, anticancer drugs. This review focuses on recent studies on such mouse strains and the insights obtained for a number of anticancer drugs. As some aspects have already been extensively reviewed previously (Iusuf et al., 2012b, c; Sprowl and Sparreboom, 2014;