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.

中文翻译：

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大鼠全身给药后布美他尼的脑内分布异质性


布美他尼被广泛用作抑制大脑中 Na-K-2Cl 协同转运蛋白 NKCC1 的工具和超说明书治疗，从而使多种脑部疾病的神经元内氯水平正常化。然而，全身给药后，布美他尼很难渗透到脑实质中，并且没有达到足以抑制 NKCC1 的水平。低脑渗透率是高电离率和血浆蛋白结合的结果，这限制了被动扩散和脑外流运输进入大脑的结果。在之前的研究中，布美他尼是在整个大脑或少数大脑区域（例如海马体）中测定的。然而，血脑屏障及其外排转运蛋白在不同的大脑区域是异质的，因此不能排除布美他尼在某些离散的大脑区域达到足够高的脑水平以抑制 NKCC1。在此，在大鼠静脉注射 10 mg/kg 布美他尼后，在 14 个脑区中测定了布美他尼。由于布美他尼在大鼠中的消除速度比人类快得多，因此用胡椒基丁醚预处理可降低布美他尼的代谢。区域布美他尼水平存在高达 5 倍的显着差异，其中中脑和嗅球水平最高，纹状体和杏仁核水平最低。脑：血浆比率范围在 0.004（杏仁核）和 0.022（嗅球）之间。区域脑水平与局部脑血流量显着相关。然而，区域布美他尼水平远低于IC 50 (2.4 μM) 先前针对大鼠 NKCC1 测定。因此，这些数据进一步证实了布美他尼在啮齿动物脑部疾病模型中的作用与脑部 NKCC1 抑制无关。