Stephanie van Hoppe

176 Chapter 8 not its oral bioavailability or liver distribution. We further found that CYP3A does affect the oral bioavailability of ponatinib in vivo . Chapter 6 reviews the impact of theOATP1A/1B family on the disposition and toxicity of anti-cancer drugs and how the recent use of knockout and humanized OATP1A/1B mouse models has helped us gain insight into the in vivo role of these OATP1A/1B transporters. We especially focused on their functional role in drug pharmacokinetics and their implications for therapeutic efficacy and toxic side effects of anti-cancer and other drug treatments. In summary, the studies presented in this thesis contribute to our current knowledge on ABC efflux transporters and CYP3A metabolizing enzymes. We demonstrated the role ABCB1 and ABCG2 play in restricting brain accumulation of theTKIs afatinib, osimertinib, ibrutinib and ponatinib by means of in vitro and in vivo experiments. We also found that while these two ABC transporters impact the oral bioavailability of afatinib, that this is not the case for the other three TKIs, whose oral bioavailability is restricted mainly due to the metabolizing Cytochrome P450 enzymes. Our studies illustrate the continued importance of using mouse models to study the transport proteins in vivo , thereby enhancing our understanding of their functions. Taking everything together, we believe there is still much to be discovered in the field of transporter proteins as well as the metabolizing enzymes, in terms of their pharmacological, but also their physiological functions.