The pharmacokinetics of letrozole in brain and brain tumor in rats with orthotopically implanted C6 glioma, assessed using intracerebral microdialysis
The pharmacokinetics of letrozole in brain and brain tumor in rats with orthotopically implanted C6 glioma, assessed using intracerebral microdialysis
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DOI：
10.1007/s00280-013-2205-y
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发表时间：
2013-08-01
影响因子：
3
通讯作者：
Desai, Pankaj B.
中科院分区：
文献类型：
--
作者：
Dave, Nimita;Gudelsky, Gary A.;Desai, Pankaj B.
新出现的证据表明，原发性和转移性脑肿瘤可能对激素操纵敏感。然而，化合物在脑中，更重要的是在脑肿瘤中针对这些靶点的药代动力学尚未得到很好的表征。在这里，我们研究了来曲唑，第三代芳香化酶抑制剂，在正常大脑和原位植入的C6胶质瘤在Sprague-Dawley大鼠的药代动力学。脑内微透析测定游离来曲唑在脑细胞外液（ECF）的浓度，同时收集血液样本（通过颈静脉）来评估血浆中来曲唑的水平。来曲唑以4、6、8和12 mg/kg的剂量静脉内给药，并在8 h内收集ECF和血液样品。为了评估正常与肿瘤脑药代动力学，将来曲唑（4或8 mg/Kg; i. v.）在脑中植入C6胶质瘤后10天施用。用双探针脑内微透析技术测定了脑内无瘤区和荷瘤区的ECF，结果表明，正常脑ECF、血浆C（max）和AUC（0-8h）随来曲唑剂量增加呈线性增加，但在12 mg/kg剂量时呈非线性增加。相对脑分布系数AUC（ECF）/AUC（血浆（ub））为0.3-0.98。肿瘤对来曲唑的摄取是无肿瘤区的1.5- 2倍，因此，来曲唑穿过血脑屏障的渗透性很高，并且暴露于脑中是剂量依赖性的。此外，脑肿瘤来曲唑水平明显高于无肿瘤区域，这强调了其对肿瘤细胞活性的潜在选择性。
Emerging evidence suggests that primary and metastatic brain tumors may be sensitive to hormonal manipulations. However, the pharmacokinetics of compounds against such targets in the brain and, more importantly, in the brain tumor are not well characterized. Here, we investigated the pharmacokinetics of letrozole, a third-generation aromatase inhibitor, in the normal brain and in orthotopically implanted C6 glioma in Sprague-Dawley rats.Intracerebral microdialysis was employed to determine the concentrations of unbound letrozole in the brain extracellular fluid (ECF) while simultaneously collecting blood samples (via jugular vein) to assess plasma levels of letrozole. Letrozole was administered intravenously at doses of 4, 6, 8 and 12 mg/kg, and ECF and blood samples were collected over 8 h. For assessing normal versus tumoral brain pharmacokinetics, letrozole (4 or 8 mg/Kg; i.v.) was administered 10 days after implantation of C6 glioma in the brain. Dual-probe intracerebral microdialysis was employed for assessing ECF samples from tumor-free and tumor-bearing regions of the brain.Normal brain ECF and plasma C (max) and AUC(0-8h) increased linearly with letrozole doses up to 8 mg/kg dose, but at 12 mg/kg, the pharmacokinetics were nonlinear. The relative brain distribution coefficients, AUC(ECF)/AUC(plasma (ub)), were 0.3-0.98. The tumoral uptake of letrozole was 1.5- to 2-fold higher relative to tumor-free region.Thus, letrozole permeability across the blood brain barrier is high, and the exposure to the brain is dose dependent. Furthermore, the brain tumoral letrozole levels are markedly higher than those in the tumor-free regions, which underscore potential selectivity of its activity against tumor cells.