Effect of blood brain barrier permeability in recurrent high grade gliomas on the intratumoral pharmacokinetics of methotrexate: a microdialysis study.
OBJECTIVE
Determining whether potentially therapeutic drug exposure is achieved within brain tumors in an exploratory clinical investigation would provide a rational basis for selecting agents for evaluation in phase II trials. This study investigated the use of microdialysis to assess intratumoral drug distribution in patients with recurrent high grade gliomas (HGG).


METHODS
Microdialysis catheters were placed during surgery for residual HGG 1-day before giving methotrexate (MTX) 12-g/m(2) by 4-h i.v. infusion. MTX was measured by Liquid Chromatography/Mass Spectrometry (LC/MS) in plasma and microdialysate during the infusion and for 24-h thereafter. Blood brain barrier (BBB) permeability of tissue in which the microdialysis probe was located was determined by digitally fusing brain CT and contrast enhanced MRI images.


RESULTS
The microdialysis probe was located in contrast enhancing tumor in two patients and nonenhancing tissue in two others. Cerebral drug penetration, as indicated by the ratio of the area under the MTX concentration-time curves in brain extracellular fluid and plasma, was considerably greater in contrast enhancing tumor (0.28-0.31) than nonenhancing tissue (0.032-0.094). Nevertheless, MTX concentrations in ECF exceeded 2-microM, the average concentration for 50% cell kill against glioma cell lines in vitro, for 20-26 h in both regions of the tumor.


CONCLUSIONS
Microdialysis is a very informative technique for characterizing the intratumoral pharmacokinetics of drugs, such as MTX, that do not freely penetrate the BBB. Establishing the catheter probe location relative to areas of BBB disruption is required to properly assess the significance of microdialysis data in this context.
Blakeley
Jaishri O
JO
Johns Hopkins University School of Medicine, Cancer Research Building II, 1550 Orleans Street, Suite 1M16, Baltimore, MD, 21231, USA. jblakel3@jhmi.edu
Olson
Jeffrey
J
Grossman
Stuart A
SA
He
Xiaoying
X
Weingart
Jon
J
Supko
Jeffrey G
JG
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008727:Methotrexate / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017551:Microdialysis / Q000379:methods; D008875:Middle Aged; D013997:Time Factors
D007166:Immunosuppressive Agents; D008727:Methotrexate
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