Quantitative assessment of P-glycoprotein function in the rat blood-brain barrier by distribution volume of [11C]verapamil measured with PET
Quantitative assessment of P-glycoprotein function in the rat blood-brain barrier by distribution volume of [11C]verapamil measured with PET
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DOI：
10.1016/s1053-8119(03)00405-1
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发表时间：
2003-11-01
期刊：
影响因子：
5.7
通讯作者：
Hendrikse, NH
中科院分区：
文献类型：
--
作者：
Bart, J;Willemsen, ATM;Hendrikse, NH
血脑屏障（BBB）是一种功能性屏障，其通过其物理解剖学性质和ATP驱动的药物外排泵（如P-糖蛋白（P-gp））的存在阻碍各种药物递送至脑。本研究的目的是（1）研究分布容积（DV）是否可用于定量131313中（标记）P-gp底物动力学，以及（2）研究P-gp调节如何影响脑DV。我们使用正电子发射断层扫描（PET）和动脉采血测量了大鼠脑中P-gp底物[C-11]维拉帕米（0.1 mg/kg）的动力学。使用0、10、15、25、35和50 mg/kg体重的环孢菌素A（CsA）作为P-gp调节剂。[C-11]维拉帕米动力学通过DV进行了很好的描述，通过非房室Logan分析进行计算。Logan分析得到了动态PET数据的极好拟合，揭示了[C-11]维拉帕米及其相关DV的可逆行为。未调节大鼠的DV为0.65 ml/ml +/- 0.23（平均值+/- SD）。用10、15、25、35和50 mg/kg CsA调节后，DV值分别增加至0.82 +/- 0.06、1.04 +/- 0.20、2.85 +/- 0.51、2.91 +/- 0.64和3.77 +/- 1.23。[C-11]维拉帕米动力学在高于25 mg/kg CsA的调节水平下可饱和。四参数Hill图拟合良好（R-2 = 0.79）。总之，[C-11]维拉帕米的DV是测量（标记）P-gp底物在BBB体内动力学的有效和有效工具。[C-11]维拉帕米的脑DV通过P-gp调节呈剂量依赖性增加。定量洞察体内P-gp调制可能是一个很有前途的一步，评估P-gp底物输送到人脑。(C)2003年爱思唯尔公司All rights reserved.
The blood-brain barrier (BBB) is a functional barrier that hampers the delivery of various drugs to the brain by its physicoanatomical properties and by the presence of ATP-driven drug efflux pumps, such as P-glycoprotein (P-gp). The aims of this study were (1) to study whether the distribution volume (DV) is useful for quantification of (labeled) P-gp substrate kinetics over the 131313 and (2) to study how brain DV is affected by P-gp modulation. We measured the kinetics of the P-gp substrate [C-11]verapamil (0.1 mg/kg) in rat brains using positron emission tomography (PET) and arterial blood sampling. Cyclosporin A (CsA) at 0, 10, 15, 25, 35, and 50 mg/kg of body weight was used as a P-gp modulator. The [C-11]verapamil kinetics were very well described by DV, computed by noncompartmental Logan analysis. Logan analysis resulted in excellent fits of dynamic PET data, revealing the reversible behavior of [C-11]verapamil and its associated DV. The DV in unmodulated rats was 0.65 ml/ml +/- 0.23 (mean +/- SD). After modulation with 10, 15, 25, 35, and 50 mg/kg of CsA, DV values increased to 0.82 +/- 0.06, 1.04 +/- 0.20, 2.85 +/- 0.51, 2.91 +/- 0.64, and 3.77 +/- 1.23, respectively. The [C-11]Verapamil kinetics were saturable at modulation levels above 25 mg/kg of CsA. The data fitted well by a four-parameter Hill plot (R-2 = 0.79). In conclusion, the DV of [C-11]verapamil is a valid and potent tool to measure the kinetics of (labeled) P-gp substrates in vivo at the BBB. The brain DV of [C-11]verapamil increases dose dependently by P-gp modulation. Quantitative insight into in vivo P-gp modulation may be a promising step toward assessment of P-gp substrate delivery to human brains. (C) 2003 Elsevier Inc. All rights reserved.