Modulation of MDR1 isoform of P-glycoprotein efflux transporter increases permeability of doxorubicin into the brain of the rat

摘要

The blood–brain barrier (BBB) is a physical and metabolic barrier between systemic circulation and thebrain. BBB maintains homeostasis and protects the brain from toxic insults but it may represent a real limitingfactor to delivering chemotherapy agents such as anthracyclines within the brain tumor mass. We have alreadydemonstrated [1] that doxorubicin concentration in the rat brain is greatly enhanced when doxorubicin isadministered in the presence of therapeutic plasma levels of morphine. Morphine is a substrate of the MDR1isoform of P-glycoprotein (P-gp) efflux transporter, which very efficiently removes several molecules and drugsfrom the CNS, thus limiting their entry into the brain. Morphine mediated "accumulation" of doxorubicin intothe brain might result from its reduced efflux mediated by P-gp at the level of BBB. Aim of the present researchwas to verify whether other drugs, known to be substrates of the MDR1 isoform of P-gp share the effect ofmorphine in allowing accumulation of anthracycline within the brain. We explored the feasibility of activemodification of the BBB in an animal model by using pretreatment with ondansetron or dexamethasone to allowdoxorubicin accumulation into the brain. Our data suggest that blockade of the MDR1 isoform of P-gp effluxtransporter by pretreatment with ondansetron or dexamethasone is able to allow doxorubicin penetration into thebrain. These preliminary results will enable us to design novel therapeutic approaches to refractory or recurrentbrain tumours in which molecules usually hindered by BBB may have a therapeutic impact