Stephanie van Hoppe

7 Preface P R E FAC E Membrane transporters are key players in the regulation of homeostasis, cell integrity and metabolism in organisms. The ATP-binding cassette (ABC) efflux transporters and Organic Anion-transporting Polypeptide (OATP) influx transporters are two main superfamilies that are expressed in pharmacologically important organs such as the liver, small intestine, kidney and the blood-brain barrier (BBB). These transporters can transport endogenous and exogenous molecules and thereby are important in the absorption, disposition, elimination and toxicity of many drugs. This thesis mainly addresses the pharmacokinetic impact of ABCB1 and ABCG2 efflux transporters and the Cytochrome P450 metabolizing enzymes on a subset of anti- cancer drugs, and we conclude with a review on the OATP1A/1B family. Chapter 1 introduces the ABC transporters and their tissue localization and their pharmacologic role in the distribution of their substrates. This chapter also introduces the Cytochrome P450 enzymes and the tyrosine kinase inhibitors (TKIs). Chapter 2 presents the role of ABCB1 and ABCG2 in the distribution of the irreversible TKI afatinib. In chapter 3 we demonstrate the importance of these ABC transporters, especially ABCB1, for brain accumulation of the irreversible TKI osimertinib and its main active metabolite AZ5104. In chapter 4 we investigate the roles ABCB1 and ABCG2, as well as CYP3A, play in the disposition of the irreversible TKI ibrutinib and its main metabolite, ibrutinib-DiOH. Chapter 5 describes the effects of the ABC transporters and CYP3A on the distribution of ponatinib and its main metabolite, DMP. Chapter 6 reviews the impact of the OATP1A/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.