The use of intracerebral microdialysis for the determination of pharmacokinetic profiles of anticancer drugs in tumor-bearing rat brain.
OBJECTIVE
The use of intracerebral microdialysis as a tool to measure the penetration of anticancer agents in brain tumor was investigated.


METHODS
Following intravenous (iv) administration of 75 mg/kg. concentration-time profiles of methotrexate (MTX) were determined in brain cortical dialysate and in plasma. The individual ratio of the area under the curve of MTX in brain dialysate over that in plasma (MTX penetration) was determined in normal brain, in tumor-bearing brain and in brain after sham tumor implantation. Individual brains were examined histologically on the presence of tumor, as well as for other factors that might influence local MTX penetration. Histological scores were related to the individual data on penetration of MTX.


RESULTS
MTX penetration values were higher in cortical brain at the site of the tumor, as compared to the levels measured in normal or sham implanted brain (mean increase to 250%). In the cortical brain contralateral to the tumor, MTX penetration values were found to be lower than in normal brain (mean reduction of 65%). Furthermore, it appeared that in the absence of tumor tissue, the presence of exudate around the probe was independently associated with increased penetration of MTX into the brain.


CONCLUSIONS
Tumor tissue appeared to be the most important parameter in changing local MTX penetration in brain after tumor implantation. In general, it is anticipated that intracerebral microdialysis combined with histological examination can be used to investigate effects of brain tumor presence on regional (periprobe) penetration of anticancer drugs into the brain.
de Lange
E C
EC
Leiden/Amsterdam Center for Drug Research, University of Leiden, Netherlands.
de Vries
J D
JD
Zurcher
C
C
Danhof
M
M
de Boer
A G
AG
Breimer
D D
DD
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics*; D017551:Microdialysis; D051381:Rats; D012208:Rhabdomyosarcoma / Q000378:metabolism*
D008727:Methotrexate