Impact of apical ABC transporters on pharmacokinetics of targeted anticancer drugs

Tyrosine kinase inhibitors (TKIs) are small molecule inhibitors that selectively interfere with the intrinsic tyrosine kinase activity of proteins in cellular signal transduction pathways and thereby block receptor autophosphorylation and activation of downstream signal transducers. TKIs are increasingly used in anticancer pharmacotherapy, often resulting in substantial improvements in overall survival and quality of life of patients. However, their usually limited accumulation in brain tissue may limit their efficacy towards malignancies in the brain. An important factor for this limited brain accumulation could be due to the presence of active drug efflux transporters such as P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2) at the blood-brain barrier (BBB). By utilizing mouse models deficient of ABCB1 and/or ABCG2, we aimed to increase the brain accumulation of TKIs in mice using several approaches, including coadministration of elacridar, a dual inhibitor of Abcb1 and Abcg2, or saturation of ABCB1 and ABCG2 with high initial plasma concentrations of drug. In this thesis, we have demonstrated the usefulness of single and combination transporter knockout mouse models to study the impact of ABCB1 and ABCG2 on oral availability and brain accumulation of drugs, including sunitinib, crizotinib and everolimus in vivo. We have also shown that concomitant use of elacridar can effectively increase brain penetration of sunitinib, N-desethyl sunitinib and crizotinib in wild-type mice, albeit slightly less effectively for N-desethyl sunitinib. In addition, we also demonstrated that a high initial plasma concentration of sunitinib can lead to partial and complete saturation of Abcb1 and Abcg2 transport activities, respectively, in the BBB of wild-type mice. Consequently, this approach resulted in highly increased brain concentrations of sunitinib in wild-type mice. By using mice heterozygous for Abcb1 and Abcg2 gene disruptions, we found that halving the amount of Abcb1 and Abcg2 at the BBB only resulted in very small (