大鼠全身用药后布美他尼在大脑中的分布不均。

IF 1.7 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Wolfgang Löscher, Martina Gramer, Kerstin Römermann
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引用次数: 0

摘要

布美他尼被广泛用作抑制脑内Na-K-2Cl共转运体NKCC1的工具和非标签疗法,从而使多种脑部疾病的神经元内氯离子水平恢复正常。然而,在全身用药后,布美他尼在脑实质内的渗透率很低,达不到足以抑制NKCC1的水平。脑渗透率低既是高电离率和血浆蛋白结合的结果,限制了通过被动扩散进入大脑,也是脑外流转运的结果。在以往的研究中,布美他尼是在全脑或海马等少数脑区进行测定的。然而,不同脑区的血脑屏障及其外流转运体是不同的,因此不能排除布美他尼在某些离散脑区达到足够高的脑内水平以抑制NKCC1的可能性。在此,我们对大鼠静脉注射10毫克/千克的布美他尼在14个脑区的含量进行了测定。由于布美他尼在大鼠体内的消除速度比人类快得多,因此在使用胡椒基丁醚进行预处理后,布美他尼的代谢速度会降低。经测定,各区域的布美他尼水平差异显著,最高可达 5 倍,其中中脑和嗅球的水平最高,纹状体和杏仁核的水平最低。脑浆比介于0.004(杏仁核)和0.022(嗅球)之间。大脑区域水平与局部脑血流量有明显的相关性。然而,区域布美他尼水平远远低于之前测定的大鼠 NKCC1 IC50(2.4 μM)。因此,这些数据进一步证实了所报道的布美他尼在啮齿类动物脑部疾病模型中的作用与大脑中的NKCC1抑制无关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Heterogeneous brain distribution of bumetanide following systemic administration in rats

Heterogeneous brain distribution of bumetanide following systemic administration in rats

Bumetanide is used widely as a tool and off-label treatment to inhibit the Na-K-2Cl cotransporter NKCC1 in the brain and thereby to normalize intra-neuronal chloride levels in several brain disorders. However, following systemic administration, bumetanide only poorly penetrates into the brain parenchyma and does not reach levels sufficient to inhibit NKCC1. The low brain penetration is a consequence of both the high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, and of brain efflux transport. In previous studies, bumetanide was determined in the whole brain or a few brain regions, such as the hippocampus. However, the blood–brain barrier and its efflux transporters are heterogeneous across brain regions, so it cannot be excluded that bumetanide reaches sufficiently high brain levels for NKCC1 inhibition in some discrete brain areas. Here, bumetanide was determined in 14 brain regions following i.v. administration of 10 mg/kg in rats. Because bumetanide is much more rapidly eliminated by rats than humans, its metabolism was reduced by pretreatment with piperonyl butoxide. Significant, up to 5-fold differences in regional bumetanide levels were determined with the highest levels in the midbrain and olfactory bulb and the lowest levels in the striatum and amygdala. Brain:plasma ratios ranged between 0.004 (amygdala) and 0.022 (olfactory bulb). Regional brain levels were significantly correlated with local cerebral blood flow. However, regional bumetanide levels were far below the IC50 (2.4 μM) determined previously for rat NKCC1. Thus, these data further substantiate that the reported effects of bumetanide in rodent models of brain disorders are not related to NKCC1 inhibition in the brain.

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来源期刊
CiteScore
3.60
自引率
0.00%
发文量
35
审稿时长
6-12 weeks
期刊介绍: Biopharmaceutics & Drug Dispositionpublishes original review articles, short communications, and reports in biopharmaceutics, drug disposition, pharmacokinetics and pharmacodynamics, especially those that have a direct relation to the drug discovery/development and the therapeutic use of drugs. These includes: - animal and human pharmacological studies that focus on therapeutic response. pharmacodynamics, and toxicity related to plasma and tissue concentrations of drugs and their metabolites, - in vitro and in vivo drug absorption, distribution, metabolism, transport, and excretion studies that facilitate investigations related to the use of drugs in man - studies on membrane transport and enzymes, including their regulation and the impact of pharmacogenomics on drug absorption and disposition, - simulation and modeling in drug discovery and development - theoretical treatises - includes themed issues and reviews and exclude manuscripts on - bioavailability studies reporting only on simple PK parameters such as Cmax, tmax and t1/2 without mechanistic interpretation - analytical methods
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