Stephanie van Hoppe

12 Chapter 1 as cardiovascular disease, ulcerative colitis, Alzheimer or cancer (2-6). In this thesis we have studied two members in particular, ABCB1 (MDR1, P-glycoprotein or P-gp) and ABCG2 (Breast Cancer Resistance Protein, BCRP), which are especially important in pharmacokinetics (7, 8). They both influence the disposition of a wide variety of endogenous and exogenous compounds, including many anticancer drugs, and can thus affect their efficacy and toxicity. For this reason, changes in the level of expression and functionality of these transporters can influence the efficacy and safety of transported drugs. ABCB1 and ABCG2 are expressed at pharmacologically important sites such as the apical membranes of enterocytes, hepatocytes and renal tubular epithelial cells, as depicted in Figure 2, where they can limit gastrointestinal absorption or mediate direct intestinal, hepatic, or renal excretion of their substrates (7, 8). Furthermore, they are both expressed in apical membranes of barriers protecting sanctuary tissues such as the blood-brain, blood-placenta and blood-testis barriers, where substrates are pumped directly out of the epithelial or endothelial cells into the blood. Consequently, many chemotherapeutic and other anticancer agents that are ABCB1 and/or ABCG2 substrates have restricted brain accumulation (7-10). Figure 2 : Schematic representation of the expression sites of ABCB1 and ABCG2 and their transport direction in pharmacologically important organs. Shown is the transport direction of the ABCB1 and ABCG2 substrates in the kidney from the proximal tubular cells into the tubular lumen (i.e., towards the urine). In the intestines ABCB1 and ABCG2 transport their substrates from the enterocytes into the intestinal lumen (i.e., towards the feces), while in the brain these efflux transporters transport their substrates from the endothelial cells into the blood. In the liver ABCB1 and ABCG2 transport their substrates from the hepatocytes into the bile, i.e., towards the intestinal lumen. C Y TO C HR OME P450 The human cytochrome P450s are a family of monooxygenases, comprising 57 genes, that catalyze the metabolism of a wide variety of endogenous and exogenous compounds including xenobiotics, drugs, environmental toxins, steroids and fatty acids. These enzymes are responsible for metabolism of approximately 60% of prescribed drugs and they are essential to maintain homeostasis (11, 12). The basic catalytic mechanism appears to be common to all CYPs and involves a two-electron reduction of molecular oxygen to form a reactive oxygen species and water. Of the human CYP enzymes, CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A4 have been described to contribute to the Phase I metabolism of the vast majority of drugs compared with other Phase I oxidative enzymes. The human CYP3A subfamily includes CYP3A4, 3A5, 3A7 and