Stephanie van Hoppe

128 Chapter 6 Tang et al., 2013), we will only briefly touch upon those. 1 . 2 . OATP1A / 1B kno c kou t and t r an s gen i c mou s e s t r a i n s c ha r a c t e r i z ed t o da t e To date, most characterized knockout and transgenic mouse models concern members of the OATP1A and OATP1B subfamilies, as these are thought to be most relevant for overall pharmacokinetics in man. Some initial studies suggested that human OATP1A2 was expressed in the intestinal epithelium, which would potentially indicate an important role in drug absorption (Glaeser et al., 2007). However, many independent later studies could not corroborate these findings, and it is now probably safe to conclude that normally there is no substantial level of OATP1A2 present in the small or large intestine of humans (e.g. Drozdzik et al., 2014). On current data, OATP1A2 is substantially expressed in cholangiocytes lining the bile ducts in the liver, in the human blood-brain barrier, in apical membranes of kidney tubules, and in a variety of human tumors (van de Steeg et al., 2013 and references therein). In contrast to OATP1A2, human OATP1B1 and OATP1B3 are highly and primarily expressed in the basolateral (sinusoidal) membrane of human hepatocytes, where they can mediate the hepatic uptake of numerous substrate compounds (e.g. Nakanishi and Tamai, 2012). As these genes are also known to be substantially affected by genetic polymorphisms and mutations in humans (e.g. Niemi et al., 2011; van de Steeg et al., 2012), they have attracted most attention. The functionally related OATP2B1 protein is also a broad- specificity multidrug-uptake transporter, especially at lower pH, and highly expressed in both intestine and the sinusoidal membrane of hepatocytes. It has therefore been suggested that it might also have considerable pharmacokinetic impact (Nakanishi and Tamai, 2012). However, to date no OATP2B1 mouse models have been published, so we will not further cover this transporter here. A complication in studying mouse models for the OATP1A/1B transporters is that there are no straightforward orthologues between the individual mouse and human Oatp1a/1b and OATP1A/1B genes. As indicated in Figure 1 , there are no less than 4 different Oatp1a genes in the mouse, Oatp1a1, Oatp1a4, Oatp1a5 and Oatp1a6, in addition to 2 Oatp1a-like elements that may be pseudo-genes. This compares with the single OATP1A2 gene in humans. On the other hand, the mouse has only one Oatp1b2 gene, contrasting with the two human OATP1B1 and OATP1B3 genes ( Figure 1 ). Although the mouse and human OATP1A proteins are obviously more similar to each other than to the mouse and human OATP1B proteins, and vice versa, the amino acid divergence within each subfamily is still considerable (as low as 67% amino acid identity within the OATP1A subfamily, and 65% within the OATP1B subfamily). Consequently, with these broad-specificity multidrug transporters, no reliable statements can bemade