Stephanie van Hoppe

14 Chapter 1 3A43, with CYP3A4 having the highest abundance in the liver, comprising between 30 and 50% of the total hepatic CYP content (13, 14). CYP3A and CYP2C represent the major intestinal CYPs, accounting for approximately 80% and 18% of the intestinal CYP content, respectively (15). CYP3A4 is therefore one of the main drug-metabolizing enzymes. It has a large and flexible active site that enables its interaction with a wide range of structurally diverse compounds and permits metabolism of (and/or inhibition by) such diverse molecules and drugs as hormones (testosterone, estrogen), anti-cancer drugs (docetaxel, tamoxifen), and anti-fungal agents (ketoconazole), amongst others (12, 16). It has been shown that inhibition of CYPs may achieve rapid increases in the blood concentration and bioavailability of drugs, but inhibition of CYPs may also lead to the toxicity or lack of efficacy of a drug (17, 18). T Y R O S I N E K I NA S E I NH I B I TO R S Conventional chemotherapy typically does not discriminate effectively between rapidly dividing normal cells (e.g., bone marrow and gastrointestinal tract) and tumor cells, thereby often leading to severe toxic side effects. Tumor responses from these kinds of cytotoxic chemotherapy are usually unpredictable. In contrast, targeted therapies interfere with defined molecular targets that have a demonstrated role in tumor growth or progression, and are often specifically located in tumor cells. Therefore, targeted therapies have a generally higher specificity towards tumor cells and thereby provide a broader therapeutic window with less toxicity (19). One of the most prominent types of targeted therapies are formed by the tyrosine kinase inhibitors (TKIs). Tyrosine kinases play a critical role in the modulation of growth factor signaling, and thus activated forms of these enzymes can cause an increase in tumor cell proliferation and growth, induce anti-apoptotic effects and promote angiogenesis and metastasis. In addition to activation by growth factors, protein kinase activation or alteration by somatic mutation is a common mechanism of tumorigenesis (20). Because all these effects are mediated by the activation of tyrosine kinase receptors, it makes these targets key for the development of their inhibitors. In this thesis we have studied the pharmacokinetics of the following TKIs: afatinib, osimertinib, ibrutinib and ponatinib. U S E S AND L I M I TAT I ON S O F MOU S E S T UD I E S Mouse studies are useful to establish basic principles governing pharmacokinetic behavior, and studies often make use of single and/or combination knockout mouse