The destiny of anti-cancer drugs: The impact of drug transporters and drug-metabolizing enzymes on the pharmacokinetics of anti-cancer therapies

Abstract

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. In this thesis we delved deeper into the pharmacological functions of ABCB1 and ABCG2 in vitro and in vivo for several anti-cancer drugs using specialized cell lines and various knockout and transgenic mouse models. We additionally looked into the pharmacological impact of CYP3A proteins which form one of the main metabolic enzyme complexes. We used various knockout and humanized mouse models to study its effects on a subset of anticancer drugs. 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 the TKIs 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.