ONDANSETRON PRE-TREATMENT FACILITATES BLOOD-BRAIN BARRIER PENETRATION OF DOXORUBICIN IN RAT MODEL

Our group recently verified that morphine pre-treatment facilitates doxorubicin delivery beyond the blood brain barrier (BBB) to the brain in the absence of signs of increased acute systemic toxicity in a rat model. Thus, it was plausible that morphine and other drugs as ondansetron inhibiting P-gp (MDR-1) localized on BBB, neurons and glial cells could increase the access of doxorubicin to the brain competing with the same efflux transporter, that very efficiently removes these drugs from the CNS. Thus, we explored the feasibility of active modification of the BBB protection, by using ondansetron pretreatment, to allow doxorubicin accumulation into the brain in an animal model. Rats were pretreated with different doses of intraperitoneal ondansetron before injection of doxorubicin (12 mg/kg). Quantitative analysis of doxorubicin was performed by mass spectrometry. Acute hearth and kidney damage was analyzed by measuring doxorubicin accumulation, LDH activity and malondialdehyde plasma levels. The concentration of doxorubicin was significantly higher in all brain areas of rats pretreated with morphine than in control tissues (P ,0.001). This was evident only at therapeutic ondansetron dose (2 mg/kg, three times over 24 hours), while lower doses were not associated with doxorubicin accumulation. Pretreatment with ondansetron did not induce an elevation of LDH activity or of lipid peroxidation compared to controls. Our data suggest that ondansetron pretreatment is able to allow doxorubicin penetration inside the brain, by modulating the blood-brain barrier. This is not associated with acute cardiac or renal toxicity. This finding might provide the rationale for clinical applications in the treatment of refractory brain tumors and pave the way to novel applications of active but currently inapplicable drugs.