Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates.
Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates.
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DOI：
10.1007/s00280-009-1085-7
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发表时间：
2010-04
影响因子：
3
通讯作者：
Fox E
中科院分区：
文献类型：
--
作者：
Jacobs S;McCully CL;Murphy RF;Bacher J;Balis FM;Fox E
顺铂、卡铂和奥沙利铂是化学反应性的抗癌药物，在脑肿瘤中具有适度的活性。先前，我们已经证明，在非人灵长类动物中，这些铂类似物在脑脊液（CSF）中的药物暴露量小于血浆超滤液（UF）药物暴露量的5%。微透析是一种微创体内方法，用于采样血液和组织细胞外液（ECF）中的小分子。本研究的目的是估计铂类似物进入脑ECF的渗透。我们使用微透析测量了非人灵长类动物脑、肌肉和血液ECF中顺铂、卡铂和奥沙利铂的游离浓度，并将血液和脑ECF中的铂浓度与使用传统采样方法获得的血浆UF和CSF浓度进行了比较。对于所有三种铂类似物，静脉微透析采样的AUC0-4h与标准血浆UF采样相似。静脉UF与血浆UF的中位AUC0-4h比值为1.1（范围0.9-1.4）。铂类似物在脑脊液和脑ECF的分布有限（5%）。脑脊液穿透预测铂类似物进入脑ECF的有限穿透，但脑脊液和脑ECF测量结果之间的一致性很差。脑脊液奥沙利铂浓度（AUC0-4h, 0.4-0.9 μM h）显著低于脑ECF浓度（AUC0-4h, 2.0-8.6 μM h）。铂类似物对脑脊液和大脑的渗透是有限的。三种铂类似物的中枢神经系统穿透性差异无临床意义。对于顺铂和卡铂，脑脊液穿透似乎是脑细胞外游离药物暴露的替代。
Cisplatin, carboplatin, and oxaliplatin are chemically reactive anticancer drugs with modest activity in brain tumors. Previously, we have demonstrated that drug exposure in cerebrospinal fluid (CSF) for these platinum analogs is <5% of the plasma ultrafiltrate (UF) drug exposure in nonhuman primates. Microdialysis is a minimally invasive in vivo method for sampling small molecules in the blood and tissue extracellular fluid (ECF). The purpose of this study was to estimate the penetration of platinum analogs into the brain ECF. We measured free concentrations of cisplatin, carboplatin, and oxaliplatin in ECF of brain, muscle, and blood of nonhuman primates using microdialysis and compared ECF platinum concentrations in blood and brain to plasma UF and CSF concentrations obtained using conventional sampling methods. For all three platinum analogs, AUC0–4h for microdialysis sampling from the vein was similar to standard plasma UF sampling. The median AUC0–4h ratio for vein to plasma UF was 1.1 (range, 0.9–1.4). The platinum analogs had limited distribution (5%) to the CSF and brain ECF. CSF penetration predicts for the limited penetration of the platinum analogs into brain ECF, but concordance between CSF and brain ECF measurements was poor. CSF oxaliplatin concentrations (AUC0–4h, 0.4–0.9 μM h) were substantially lower than brain ECF concentrations (AUC0–4h, 2.0–8.6 μM h). The penetration of platinum analogs into CSF and brain is limited. The differences in the CNS penetrations among the three platinum analogs are not clinically significant. For cisplatin and carboplatin, CSF penetration appears to be a surrogate for brain extracellular free drug exposure.
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影响因子：
11.5
作者：
Jacobs, SS;Fox, E;Balis, FM
通讯作者：
Balis, FM
影响因子：
3.9
作者：
Gupta, A;Chatelain, P;Hammarlund-Udenaes, M
通讯作者：
Hammarlund-Udenaes, M
影响因子：
6.2
作者：
Blumenthal, Deborah T.;Rankin, Cathryn;Petersdorf, Stephen H.
通讯作者：
Petersdorf, Stephen H.
影响因子：
3
作者：
Meany, Holly J.;Fox, Elizabeth;Balis, Frank M.
通讯作者：
Balis, Frank M.
影响因子：
3.3
作者：
Nakashima, M;Shibata, S;Ichikawa, M
通讯作者：
Ichikawa, M