The blood-brain barrier (BBB) is a physical and metabolic barrier between systemic circulation and the brain. BBB maintains homeostasis and protects the brain from toxic insults but it may represent a real limiting factor to delivering chemotherapy agents such as anthracyclines within the brain tumor mass. We have already demonstrated [1] that doxorubicin concentration in the rat brain is greatly enhanced when doxorubicin is administered in the presence of therapeutic plasma levels of morphine. Morphine is a substrate of the MDR1 isoform of P-glycoprotein (P-gp) efflux transporter, which very efficiently removes several molecules and drugs from the CNS, thus limiting their entry into the brain. Morphine mediated "accumulation" of doxorubicin into the brain might result from its reduced efflux mediated by P-gp at the level of BBB. Aim of the present research was to verify whether other drugs, known to be substrates of the MDR1 isoform of P-gp share the effect of morphine in allowing accumulation of anthracycline within the brain. We explored the feasibility of active modification of the BBB in an animal model by using pretreatment with ondansetron or dexamethasone to allow doxorubicin accumulation into the brain. Our data suggest that blockade of the MDR1 isoform of P-gp efflux transporter by pretreatment with ondansetron or dexamethasone is able to allow doxorubicin penetration into the brain. These preliminary results will enable us to design novel therapeutic approaches to refractory or recurrent brain tumours in which molecules usually hindered by BBB may have a therapeutic impact
Modulation of MDR1 isoform of P-glycoprotein effluxtransporter increases permeability of doxorubicin into the brain of the rat / Giovannini, MG; la Marca, G; Malvagia, S; Fratoni, V; Cardellicchio, S; Guerrini, R; de Martino, M; Genitori, L; Sardi, I. - ELETTRONICO. - (2013), pp. 115-117. (Intervento presentato al convegno 6th European Congress of Pharmacology tenutosi a Granada (Spain) nel July 17th-20th, 2012).
Modulation of MDR1 isoform of P-glycoprotein effluxtransporter increases permeability of doxorubicin into the brain of the rat
GIOVANNINI, MARIA GRAZIA;LA MARCA, GIANCARLO;GUERRINI, RENZO;DE MARTINO, MAURIZIO;
2013
Abstract
The blood-brain barrier (BBB) is a physical and metabolic barrier between systemic circulation and the brain. BBB maintains homeostasis and protects the brain from toxic insults but it may represent a real limiting factor to delivering chemotherapy agents such as anthracyclines within the brain tumor mass. We have already demonstrated [1] that doxorubicin concentration in the rat brain is greatly enhanced when doxorubicin is administered in the presence of therapeutic plasma levels of morphine. Morphine is a substrate of the MDR1 isoform of P-glycoprotein (P-gp) efflux transporter, which very efficiently removes several molecules and drugs from the CNS, thus limiting their entry into the brain. Morphine mediated "accumulation" of doxorubicin into the brain might result from its reduced efflux mediated by P-gp at the level of BBB. Aim of the present research was to verify whether other drugs, known to be substrates of the MDR1 isoform of P-gp share the effect of morphine in allowing accumulation of anthracycline within the brain. We explored the feasibility of active modification of the BBB in an animal model by using pretreatment with ondansetron or dexamethasone to allow doxorubicin accumulation into the brain. Our data suggest that blockade of the MDR1 isoform of P-gp efflux transporter by pretreatment with ondansetron or dexamethasone is able to allow doxorubicin penetration into the brain. These preliminary results will enable us to design novel therapeutic approaches to refractory or recurrent brain tumours in which molecules usually hindered by BBB may have a therapeutic impactFile | Dimensione | Formato | |
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