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Lange, Elizabeth C. M. de; Vries, Jonkman-de; Zürcher, C.; Danhof, Meindert; Boer, A.G. de; Breimer, D. D.

doi:10.1023/a:1016239822287

Cited by 41 publications

(8 citation statements)

References 15 publications

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“…Cerebral drug penetration was considerably greater in contrast enhancing regions of the tumor (28%–31%) than nonenhancing tissue (3.2%–9.4%). Interestingly, these findings are very similar to the cerebral penetration of MTX determined by microdialysis in brain tumor and normal brain tissue in rats [22]. Considering that MTX is 54%–59% protein bound in human plasma [33, 34] it appears that interstitial concentrations achieved in regions of BBB disruption are effectively limited by the free fraction of drug in systemic blood.…”

Section: Discussionsupporting

confidence: 69%

“…Methotrexate was chosen as the agent for this investigation because the feasibility of using microdialysis to characterize its intratumoral pharmacokinetics had been demonstrated in preclinical studies and assays for MTX detection are well developed [22–25]. The findings described in this report confirm that microdialysis is indeed a practical and highly informative technique in brain tumors in vivo.…”

Section: Introductionsupporting

confidence: 55%

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

et al. 2008

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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.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionsupporting

confidence: 55%

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

et al. 2008

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“…An excellent example of such sampling is a report by de Lange et al (31, 32), who examined differences in the distributions of an intravenous injection of methotrexate in tumor versus healthy brain tissue. Microdialysis sampling has also been used to investigate the metabolism of drugs and neuropeptides in specific areas of the brain (33–35).…”

Section: In Vivo Methods For Studying Transport Of Substances Acromentioning

confidence: 99%

Analytical and Biological Methods for Probing the Blood-Brain Barrier

Sloan

Nandi

Linz³

et al. 2012

Annual Rev. Anal. Chem.

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The blood-brain barrier (BBB) is an important interface between the peripheral and central nervous systems. It protects the brain against the infiltration of harmful substances and regulates the permeation of beneficial endogenous substances from the blood into the extracellular fluid of the brain. It can also present a major obstacle in the development of drugs that are targeted for the central nervous system. Several methods have been developed to investigate the transport and metabolism of drugs, peptides, and endogenous compounds at the BBB. In vivo methods include intravenous injection, brain perfusion, positron emission tomography, and microdialysis sampling. Researchers have also developed in vitro cell-culture models that can be employed to investigate transport and metabolism at the BBB without the complication of systemic involvement. All these methods require sensitive and selective analytical methods to monitor the transport and metabolism of the compounds of interest at the BBB.

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“…The trade off is that small volumes of dialysate (in the microliter range) are collected in each sample. Highly sensitive analytical methods such as HPLC and tandem mass spectrometry are then needed to detect minute concentrations of drug [63,64]. …”

Section: Body: Intratumoral Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

Microdialysis for assessing intratumoral drug disposition in brain cancers: a tool for rational drug development

Blakeley

Portnow

2010

Expert Opinion on Drug Metabolism & Toxicology

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Importance of the field: Many promising targeted agents and combination therapies are being investigated for brain cancer. However, the results from recent clinical trials have been disappointing. A better understanding of the disposition of drug in the brain early in drug development would facilitate appropriate channeling of new drugs into brain cancer clinical trials. Areas covered in this review: Barriers to successful drug activity against brain cancer and issues affecting intratumoral drug concentrations are reviewed. The use of the microdialysis technique for extracellular fluid (ECF) sampling and its application to drug distribution studies in brain are reviewed using published literature from 1995 to the present. The benefits and limitations of microdialysis for performing neuorpharmacokinetic (nPK) and neuropharmacodynamic (nPD) studies are discussed. What the reader will gain: The reader will gain an appreciation of the challenges involved in identifying agents likely to have efficacy in brain cancer, an understanding of the general principles of microdialysis, and the power and limitations of using this technique in early drug development for brain cancer therapies. Take home message: A major factor preventing efficacy of anti-brain cancer drugs is limited access to tumor. Intracerebral microdialysis allows sampling of drug in the brain ECF. The resulting nPK/nPD data can aid in the rational selection of drugs for investigation in brain tumor clinical trials.

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Untitled

Cited by 41 publications

References 15 publications

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

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

Analytical and Biological Methods for Probing the Blood-Brain Barrier

Microdialysis for assessing intratumoral drug disposition in brain cancers: a tool for rational drug development

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