Detection of doxorubicin hydrochloride accumulation in the rat brain after morphine treatment by mass spectrometry.
OBJECTIVE
The blood-brain barrier discriminates the access of several molecules to the brain. This hampers the use of some drugs, as doxorubicin, potentially active for treatment of brain tumors. We explored the feasibility of active modification of the blood-brain barrier protection, by using morphine pretreatment, to allow doxorubicin accumulation in the brain in an animal model.


METHODS
Rats were pretreated with different doses of intraperitoneal morphine before injection of doxorubicin (12 mg/kg). Quantitative analysis of doxorubicin was performed by mass spectrometry. Acute heart and kidney damage was analyzed by measuring doxorubicin accumulation, LDH activity and malondialdehyde plasma levels.


RESULTS
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 morphine dose (10 mg/kg, three times over 24 h), while lower doses (2.5 and 5 mg/kg) were not associated with doxorubicin accumulation. Pretreatment with morphine did not induce an elevation of LDH activity or of lipid peroxidation compared to controls.


CONCLUSIONS
Our data suggest that morphine 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. These preliminary results will enable us to generate novel therapeutic approaches to refractory or recurrent brain tumors, and might be useful in other human diseases of the central nervous system in which molecules usually stopped by the blood-brain barrier may have a therapeutic impact.
Sardi
Iacopo
I
Department of Onco-Hematology and Neuro-Surgery Units, A Meyer Children's Hospital, viale G Pieraccini 24, 50139 Florence, Italy. i.sardi@meyer.it
la Marca
Giancarlo
G
Giovannini
Maria Grazia
MG
Malvagia
Sabrina
S
Guerrini
Renzo
R
Genitori
Lorenzo
L
Massimino
Maura
M
Aricò
Maurizio
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004317:Doxorubicin / Q000493:pharmacokinetics*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000097:blood / Q000494:pharmacology*; D009294:Narcotics / Q000097:blood / Q000494:pharmacology*; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry
D000903:Antibiotics, Antineoplastic; D009294:Narcotics; D009020:Morphine; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase