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/m2 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-μM, 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.

Microdialysis Study of Cefotaxime Cerebral Distribution in Patients with Acute Brain Injury

“…In humans, feasibility issues of brain microdialysis restrict its use, and this technique concerns only patients who require surgery for brain tumor resection (10) or cerebral metabolism monitoring in neurointensive care units (11). The main advantage in intracerebral microdialysis is to measure continuously brain unbound concentrations as a function of time; the comparison of these brain concentrations with unbound plasma concentrations may provide information on drug transport across the BBB (12).…”

Brain Microdialysis Study of Meropenem in Two Patients with Acute Brain Injury

“…Microdialysis is a well-established technique that has been used to characterize the distribution of many drugs, including antibiotics (12), in various tissues, including brain tissue, in both animals (4) and humans. However, only very few microdialysis studies have been conducted with humans to characterize the brain distribution of exogenous compounds, either in patients requiring surgery for brain tumor resection (1,14) or in neurotrauma patients undergoing brain microdialysis for intensive-care monitoring (3,7). Not only are there limited numbers of patients potentially eligible for such studies, but also the technical difficulties requiring well-trained multidisciplinary teams limit such studies (1,3,14).…”

“…However, only very few microdialysis studies have been conducted with humans to characterize the brain distribution of exogenous compounds, either in patients requiring surgery for brain tumor resection (1,14) or in neurotrauma patients undergoing brain microdialysis for intensive-care monitoring (3,7). Not only are there limited numbers of patients potentially eligible for such studies, but also the technical difficulties requiring well-trained multidisciplinary teams limit such studies (1,3,14). Although with endogenous compounds such as lactate, pyruvate, or glucose, variations from baseline values are normally monitored, concentrations of exogenous compounds must be expressed in absolute terms.…”

Microdialysis Combined with Proteomics for Protein Identification in Breast Tumor Microenvironment In Vivo

“…Microdialysis is considered as a minimally invasive procedure and has also been successfully performed in a variety of human tissues, such as normal breast tissue and breast tumors [13], pelvic peritoneum [38], flap reconstructions [39], abdominal adipose tissue [40], brain tumors [41], forearm skin [42], and renal tissue [43]. Microdialysis combined with proteomics will likely be performed in human breast cancer in the future, yielding complementary molecular profiles comparing these results with those obtained from ductal lavage and nipple aspirate fluid samples.…”