Stephanie van Hoppe

158 Chapter 6 strongly between cell types. There may also be substrate-specific competitive or non- competitive inhibition or stimulation of transport of certain substrates by an OATP by some compounds abundant in some cell types, but not in others. In fact, heterotropic or even homotropic cooperativity phenomena are quite common for multidrug- handling proteins like CYP3A (Ekroos and Sjogren, 2006; Harlow and Halpert, 1998) or multispecific ABC transporters like P-glycoprotein (ABCB1) and ABCC2 (Aller et al., 2009; Bakos et al., 2000; Huisman et al., 2002; Kondratov et al., 2001; Shapiro and Ling, 1998; Zelcer et al., 2003), and this might also apply to the multidrug-handling OATPs. Indeed, a number of compounds have been identified that can stimulate OATP-mediated uptake of some, but not all known substrates of OATP1B1 and/or OATP1B3 (e.g. Gui et al., 2008; Ohnishi et al., 2014; Roth et al., 2011). If the presence of such (endogenous) co- stimulatory or inhibitory molecules differs between cell types, they may also affect the apparent substrate specificity of OATPs between cell types. Differential pH-dependent uptake of various substrates by OATPs (e.g. Leuthold et al., 2009; Martinez-Becerra et al., 2011; Oostendorp et al., 2009) can perhaps sometimes play a role, and there may be other mechanisms involved that have not been realized yet. Resolving these aspects will present an interesting area for future research into OATP functioning. 5 . Con c lud i ng r ema r k s and f u t ur e p e r s p e c t i v e With this review we have aimed to provide a number of illustrations of how the recent use of knockout and transgenic (humanized) Oatp1a/1b and OATP1A/1B mouse strains has helped us to gain insight into the in vivo functioning of OATP1A/1B transporters, especially with respect to antitumor agents. Apart from their pharmacokinetic and toxicological functions, also a number of physiological functions of OATP1A/1B proteins have been further elucidated, as well as their interaction with several other transporters, although clearly more work needs to be done in this area. We further touched upon possible pitfalls that can occur during the use of these mouse models, such as the up- (and down-)regulation of a number of carboxylesterase genes in the knockout and transgenic mice. Nonetheless, we think we can safely state that, when used judiciously, these mouse models can yield a wealth of information on the in vivo functions of OATP1A/1B proteins. We would like to point out that, while our opinion is that these mouse models are extremely powerful in elucidating principles of in vivo OATP1A/1B functions, one should still use the utmost caution in directly extrapolating from findings in the humanized mouse models to the situation in human patients. An important reason for this is that, even while one may have reproduced the right level of expression and activity of a