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
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DOI：
10.1007/s11060-008-9678-2
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发表时间：
2009-01-01
影响因子：
3.9
通讯作者：
Supko, Jeffrey G.
中科院分区：
文献类型：
--
作者：
Blakeley, Jaishri O.;Olson, Jeffrey;Supko, Jeffrey G.
目的：在探索性临床研究中确定脑肿瘤内是否实现了潜在的治疗药物暴露，将为选择用于 II 期试验评估的药物提供合理的基础。本研究调查了使用微透析来评估复发性高级别神经胶质瘤 (HGG) 患者的瘤内药物分布。患者和方法：手术期间放置微透析导管以清除残留的 HGG，然后静脉注射甲氨蝶呤 (MTX) 12g/m 2 4 小时。输液。在输注期间和输注后 24 小时内，通过液相色谱/质谱 (LC/MS) 测量血浆和微透析液中的 MTX。通过数字融合脑 CT 和对比增强 MRI 图像来确定微透析探针所在组织的血脑屏障 (BBB) 通透性。结果：微透析探针位于两名患者的对比增强肿瘤中，以及另外两名患者的非增强组织中。脑细胞外液和血浆中 MTX 浓度-时间曲线下面积的比率表明，脑药物渗透在对比增强肿瘤中 (0.28-0.31) 明显大于非增强组织 (0.032-0.094)。尽管如此，ECF 中的 MTX 浓度超过了 2-muM，这是体外对神经胶质瘤细胞系杀死 50% 细胞的平均浓度，持续 20-26 小时，在肿瘤的两个区域中。结论：微透析是一种信息丰富的技术，可用于表征不能自由穿透 BBB 的药物（例如 MTX）的瘤内药代动力学。需要建立相对于 BBB 破坏区域的导管探针位置，才能正确评估微透析数据在这种情况下的重要性。
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) 12g/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-mu M, 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.