Effect of blood brain barrier permeability in recurrent high grade gliomas on the intratumoral pharmacokinetics of methotrexate: a microdialysis study

Abstract

Purpose: 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).

Patients and 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.

Fig. 1

Coronal view of digitally fused gadopentetic acid contrast enhanced brain MRI and nonenhanced head CT images of the four patients who completed the study. A gold filament in the tip of the microdialysis catheter enables visualization of the probe location in the CT scan. The microdialysis probe tip was located in contrast enhancing tissue in patients A and B and in nonenhancing tissue in patients C and D. The catheter was placed in tissue near the margin of the surgical cavity following resection of the tumor in patients A, C, and D, and in tumor accessed through the biopsy burr hole in patient B

Fig. 2

Time courses of the MTX concentration in plasma (○) and brain ECF (◊). The plasma profiles are similar in each of the four patients, with peak drug levels ranging from 1,321 to 1,407-μM at the end of the 4-h i.v. infusion of MTX 12 g/m². Time courses of MTX in ECF are dependent upon whether the probe of the microdialysis catheter was placed in contrast enhancing (patients A and B) or nonenhancing (patients C and D) regions of the tumor