Improved delivery of molecularly targeted agents upon modulation of multidrug resistance efflux proteins at mouse blood brain barrier
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Recurrent brain tumors are one of the most lethal forms of solid tumors with poor prognosis. Molecularly targeted therapy, inhibiting the tyrosine kinase domain of epidermal growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptors (VEGFR) is at the forefront of current clinical practice for management of highly vascularized brain tumors. However, current molecularly targeted agents used in clinical trials so far have shown limited clinical benefit to block tumor progression. It has now been well established that P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are the two major efflux proteins that restrict the entry of xenobiotics across BBB. Overexpression of these efflux pumps in brain tumors at the BBB further compromises brain penetration of anti-tumor agents. The broad objective of this dissertation project is to study the role of efflux on brain penetration of selected small molecule tyrosine kinase inhibitors; pazopanib and vandetanib. In vitro and in vivo results showed that the entry across the BBB for these drugs is limited via active efflux. This could be a plausible mechanism for inefficacy seen for these drugs in clinical trials when used as monotherapy. As a secondary aim of this investigation we wanted to develop a viable strategy to overcome efflux at the BBB by coadministering clinically relevant efflux modulators which could also impart a synergistic pharmacological effect in the treatment regimen. Erlotinib, canertinib, everolimus and temsirolimus were screened as potential modulators of P-gp and Bcrp1 activity. The fact that these drugs inhibit a different class of receptor population than pazopanib and vandetanib, offer a dual advantage for synergistic pharmacological effect in addition to the primary role of efflux modulation. Our results demonstrate that co-administration of selected clinically relevant efflux modulators can significantly enhance brain partitioning of pazopanib and vandetanib in mice and hence warrant further pre-clinical and clinical investigation.
Table of Contents
Introduction -- Literature review -- Determination of pazopanib (gw-786034) in mouse plasma and brain tissue homogenate by high performance liquid chromatography-tandem mass spectrometry (hplc.ms-ms) -- P-glycoprotein and breast cancer resistance protein together limit brain accumulation of pazopanib; a multi-targeted tyrosine kinase inhibitor -- Differential impact of p-gp and bcrpi on brain disposition and plasma pharmacokinetics of vandetanib -- Enhanced brain accumulation of pazopanib by modulation of mdr efflus at bbb canertinib or erlotinib -- A co-administration strategy to enhance brain accumulation of vandetanib by modulation of mdr efflux at bbb by m-tor pathway inhibitors -- Effect of short term and chronic administration of sutherlandia frutescens on pharmacokinetics of nevirapine in rats -- Summary and recommendations -- Appendix