Active transport and CNS delivery of novel tyrosine kinase inhibitors.

University of Minnesota Ph.D. dissertation. March 2009. Major: Pharmaceutics. Advisor: Dr. William Elmquist. 1 computer file (PDF); xi, 197 pages.Tyrosine kinase inhibitors (TKIs) are promising agents for specific inhibition of malignant cell growth and metastasis formation. They directly interfere with TK enzymes that are activated in tumor cells and are critical to tumor growth. The success of the first generation TKI, imatinib, in the treatment of CML has led to the broader examination of its application in the treatment of other tumors, such as glioma. However, early studies showed imatinib has difficulty penetrating blood-brain barrier (BBB). One component of the BBB that may limit the delivery of imatinib into the CNS is the drug efflux transporters, such as ABCB1 (p-glycoprotein) and ABCG2 (breast cancer resistance protein). Dasatinib is a second-generation TKI developed to overcome the molecular resistance to imatinib and may be very promising in the treatment of brain tumor. Thus far little information is known about the CNS delivery of dasatinib, including the action of relevant BBB transporters in modulating this delivery. The objectives of this work were to assess the influence of various drug efflux transporters, such as ABCB1 and ABCG2, on the specific delivery of imatinib and dasatinib to CNS and the possibility of improving CNS delivery of imatinib and dasatinib by effective pharmacological inhibition. In in vitro studies, we demonstrated that imatinib is a substrate of Abcg2 by using cellular accumulation and permeability methods. In in vivo studies, we further explored that ABCB1and ABCG2 together play an important role in limiting the CNS delivery of imatinib. Saturation or inhibition of ABCB1 and ABCG2 could effectively improve CNS delivery of imatinib. In vitro evidence pointed that dasatinib is a substrate of ABCB1 and Abcg2. In vivo results revealed that the CNS delivery of dasatinib was low. ABCB1 and ABCG2 could be a factor limiting the CNS delivery of dasatinib. ABCB1 plays a more important role than ABCG2 in effecting the CNS delivery of dasatinib. The use of potent inhibitors for both ABCB1 and ABCG2 can improve dasatinib CNS delivery. These findings provide significant insight into current and new clinical strategies to more effectively use the TKIs for CNS disease treatment and prevention