The neuropharmacokinetics of temozolomide in patients with resectable brain tumors: potential implications for the current approach to chemoradiation.
The neuropharmacokinetics of temozolomide in patients with resectable brain tumors: potential implications for the current approach to chemoradiation.
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DOI：
10.1158/1078-0432.ccr-09-1349
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发表时间：
2009-11-15
期刊：
影响因子：
--
通讯作者：
Synold TW
中科院分区：
文献类型：
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作者：
Portnow J;Badie B;Chen M;Liu A;Blanchard S;Synold TW
脑内微透析（ICMD）是一种公认的监测急性脑损伤后神经化学变化的方法。本初步研究的目的是确定使用ICMD检查口服给药后替莫唑胺（TMZ）在脑皮质（BI）中的神经药代动力学（nPK）的可行性。原发性或转移性脑肿瘤患者在手术减瘤时将微透析导管置于瘤周脑组织中。CT扫描确认了导管位置。患者在术后第一天接受单次口服TMZ（150 mg/m2），在24小时内收集系列血浆和ICMD样本，并通过串联质谱法测定TMZ浓度。入组了9例患者。成功采集了9例患者中7例的透析液和血浆样本。血浆和BI中TMZ的平均浓度-时间曲线下面积（AUC）分别为17.1和2.7 μg/ml × hr，平均BI/血浆AUC比为17.8%。脑内TMZ平均峰浓度为0.6 ± 0.3 μg/ml，脑内达峰时间平均为2.0 ± 0.8小时。使用ICMD测量全身给药化疗的nPK是安全可行的。通过ICMD获得的BI中TMZ浓度与临床前ICMD模型以及脑脊液临床研究中获得的已发表数据一致。然而，在脑中达到最大TMZ浓度所需的延迟时间表明，目前的放化疗方案可以通过在放疗前2-3小时给予TMZ来改善。
Intracerebral microdialysis (ICMD) is an accepted methodology for monitoring changes in neurochemistry from acute brain injury. The goal of this pilot study was to determine the feasibility of using ICMD to examine the neuropharmacokinetics (nPK) of temozolomide (TMZ) in brain interstitium (BI) following oral administration. Patients with primary or metastatic brain tumors had a microdialysis catheter placed in peritumoral brain tissue at the time of surgical debulking. CT scan confirmed the catheter location. Patients received a single oral dose of TMZ (150 mg/m2) on the first post-operative day, serial plasma and ICMD samples were collected over 24 hrs, and TMZ concentrations were determined by tandem mass spectrometry. Nine patients were enrolled. Dialysate and plasma samples were successfully collected from 7 of the 9 patients. The mean TMZ area-under-the-concentration-time-curve (AUC) in plasma and BI were 17.1 and 2.7 μg/ml × hr, with an average BI/plasma AUC ratio of 17.8%. The mean peak TMZ concentration in brain was 0.6 ± 0.3 μg/ml, and the mean time to reach peak level in brain was 2.0 ± 0.8 hrs. The use of ICMD to measure the nPK of systemically administered chemotherapy is safe and feasible. Concentrations of TMZ in BI obtained by ICMD are consistent with published data obtained in a pre-clinical ICMD model, as well as from clinical studies of cerebrospinal fluid. However, the delayed time required to achieve maximum TMZ concentrations in brain suggests that current chemoradiation regimens may be improved by administering TMZ 2-3 hours before radiation.