Diurnal variation in P-glycoprotein-mediated transport and cerebrospinal fluid turnover in the brain.
Diurnal variation in P-glycoprotein-mediated transport and cerebrospinal fluid turnover in the brain.
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DOI：
10.1208/s12248-014-9625-4
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发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
de Lange EC
中科院分区：
文献类型：
--
作者：
Kervezee L;Hartman R;van den Berg DJ;Shimizu S;Emoto-Yamamoto Y;Meijer JH;de Lange EC
几乎所有的身体过程都表现出昼夜节律。因此，药物的药代动力学和药效学特性也可能随一天中的时间而变化。本研究的目的是研究昼夜变化的过程中，调节药物浓度在大脑中，重点是P-糖蛋白（P-gp）。这种外排转运蛋白限制了许多药物在大脑中的分布。为此，在24小时内的6个不同时间点，测定大鼠静脉给药后血浆和脑组织中P-gp底物奎尼丁的暴露量。我们的研究结果表明，给药时间显着影响暴露于奎尼丁在大脑中。在抑制P-gp后，脑组织中奎尼丁的暴露在24小时内是恒定的。为了更深入地了解过程中调节脑浓度，我们使用脑内微透析，以确定奎尼丁在脑细胞外液（ECF）和脑脊液（CSF）静脉给药后，在两个不同的时间点的浓度。使用NONMEM通过基于生理学的药代动力学建模分析数据。该模型表明，这种变化是由于在活动期间，P-gp介导的从脑深部室到血浆室的转运活性较高。此外，分析表明，与活动期相比，静息期的CSF通量更高。总之，我们表明，暴露于P-gp底物在大脑中取决于给药的时间，从而提供了一种新的策略，药物靶向大脑。本文的在线版本（doi：10.1208/s12248-014-9625-4）包含补充材料，可供授权用户使用。
Nearly all bodily processes exhibit circadian rhythmicity. As a consequence, the pharmacokinetic and pharmacodynamic properties of a drug may also vary with time of day. The objective of this study was to investigate diurnal variation in processes that regulate drug concentrations in the brain, focusing on P-glycoprotein (P-gp). This efflux transporter limits the distribution of many drugs in the brain. To this end, the exposure to the P-gp substrate quinidine was determined in the plasma and brain tissue after intravenous administration in rats at six different time points over the 24-h period. Our results indicate that time of administration significantly affects the exposure to quinidine in the brain. Upon inhibition of P-gp, exposure to quinidine in brain tissue is constant over the 24-h period. To gain more insight into processes regulating brain concentrations, we used intracerebral microdialysis to determine the concentration of quinidine in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) after intravenous administration at two different time points. The data were analyzed by physiologically based pharmacokinetic modeling using NONMEM. The model shows that the variation is due to higher activity of P-gp-mediated transport from the deep brain compartment to the plasma compartment during the active period. Furthermore, the analysis reveals that CSF flux is higher in the resting period compared to the active period. In conclusion, we show that the exposure to a P-gp substrate in the brain depends on time of administration, thereby providing a new strategy for drug targeting to the brain. The online version of this article (doi:10.1208/s12248-014-9625-4) contains supplementary material, which is available to authorized users.
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影响因子：
4.4
作者：
Lazarowski, Alberto;Caltana, Laura;Brusco, Alicia
通讯作者：
Brusco, Alicia
影响因子：
4.5
作者：
Syvanen, Stina;Schenke, Maarten;de lange, Elizabeth C.
通讯作者：
de lange, Elizabeth C.
DOI：
10.2967/jnumed.109.063289
发表时间：
2009-12
期刊：
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
影响因子：
--
作者：
Wagner CC;Bauer M;Karch R;Feurstein T;Kopp S;Chiba P;Kletter K;Löscher W;Müller M;Zeitlinger M;Langer O
通讯作者：
Langer O
影响因子：
13.9
作者：
Mohawk JA;Green CB;Takahashi JS
通讯作者：
Takahashi JS
影响因子：
64.5
作者：
SCHINKEL, AH;SMIT, JJM;BORST, P
通讯作者：
BORST, P