Antibody pharmacokinetics in rat brain determined using microdialysis
Antibody pharmacokinetics in rat brain determined using microdialysis
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DOI：
10.1080/19420862.2018.1473910
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发表时间：
2018-01-01
期刊：
影响因子：
5.3
通讯作者：
Shah, Dhaval K.
中科院分区：
文献类型：
--
作者：
Chang, Hsueh-Yuan;Morrow, Kasey;Shah, Dhaval K.
在这里，我们提出了第一个案例研究，其中微透析被用来研究抗体在大鼠大脑不同区域的药代动力学。内源性免疫球蛋白用于了解抗体在稳态时的处置情况，外源性曲妥珠单抗用于了解抗体在动态环境中的处置情况。收集纹状体(ST)、侧脑室(LV)和枕大池(CM)的微透析标本，以及血浆和脑匀浆，以全面了解抗体在脑内的药代动力学。脑脊液(CSF)中的抗体浓度因采集部位的不同而不同，其中CM的浓度比LV高几倍。此外，脑脊液中的抗体浓度(CM/LV)不能准确地反映脑实质内的抗体浓度(如ST)。CM对CSF的清除慢于LV，抗体从ST的进出也慢。外源性抗体的药代动力学研究表明，抗体通过血-脑脊液屏障进入左室可能是抗体进入脑的早期途径。血浆抗体浓度分别是左室、心肌、ST和脑匀浆抗体浓度的247~667、104~184、165~435和377~909倍。研究发现，用微透析法测量抗体在大脑不同区域的药代动力学，为了解抗体在大脑中的分布提供了前所未有的视角。这种洞察力有助于设计更好的分子、给药方案和给药途径，这反过来可以提高抗体对中枢神经系统疾病的疗效。
Here, we present the first case-study where microdialysis is used to investigate the pharmacokinetics of antibody in different regions of rat brain. Endogenous IgG was used to understand antibody disposition at steady-state and exogenously administered trastuzumab was used to understand the disposition in a dynamic setting. Microdialysis samples from the striatum (ST), lateral ventricle (LV), and cisterna magna (CM) were collected, along with plasma and brain homogenate, to comprehensively understand brain pharmacokinetics of antibodies. Antibody concentrations in cerebrospinal fluid (CSF) were found to vary based on the site-of-collection, where CM concentrations were several-fold higher than LV. In addition, antibody concentrations in CSF (CM/LV) were found to not accurately represent the concentrations of antibody inside brain parenchyma (e.g., ST). Elimination of CSF from CM was found to be slower than LV, and the entry and exit of antibody from ST was also slower. Pharmacokinetics of exogenously administered antibody revealed that the entry of antibody into LV via the blood-CSF barrier may represent an early pathway for antibody entry into the brain. Plasma concentrations of antibody were 247-667, 104-184, 165-435, and 377-909 fold higher than the antibody concentrations in LV, CM, ST, and brain homogenate. It was found that the measurement of antibody pharmacokinetics in different regions of the brain using microdialysis provides an unprecedented insight into brain disposition of antibody. This insight can help in designing better molecules, dosing regimens, and route of administration, which can in turn improve the efficacy of antibodies for central nervous system disorders.