High-Dose Acetaminophen Alters the Integrity of the Blood-Brain Barrier and Leads to Increased CNS Uptake of Codeine in Rats.
High-Dose Acetaminophen Alters the Integrity of the Blood-Brain Barrier and Leads to Increased CNS Uptake of Codeine in Rats.
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DOI：
10.3390/pharmaceutics14050949
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发表时间：
2022-04-27
期刊：
影响因子：
5.4
通讯作者：
Ronaldson, Patrick T.
中科院分区：
文献类型：
--
作者：
Yang, Junzhi;Betterton, Robert D.;Williams, Erica, I;Stanton, Joshua A.;Reddell, Elizabeth S.;Ogbonnaya, Chidinma E.;Dorn, Emma;Davis, Thomas P.;Lochhead, Jeffrey J.;Ronaldson, Patrick T.
对乙酰氨基酚（APAP）的消耗可诱导人类受试者的神经系统变化;然而，APAP对血脑屏障（BBB）完整性的影响尚不清楚。APAP引起的BBB变化可能对共同给药药物的脑递送产生深远的影响。为了研究APAP效应，向雌性Sprague-Dawley大鼠（12-16周龄）施用载体（即，100%二甲基亚砜（DMSO），腹膜内（i. p.）或APAP（80 mg/kg或500 mg/kg的DMSO溶液，i. p.;对于70 kg的人受试者，相当于900 mg或5600 mg的日剂量）。通过使用[14 C]蔗糖和[3 H]可待因的原位脑灌注测量BBB渗透性，[3 H]可待因是一种与APAP共同施用的阿片类镇痛药物（即，泰诺#3）。紧密连接蛋白的定位和蛋白表达（即，claudin-5，occludin，ZO-1）在大鼠脑微血管中的表达。仅用500 mg/kg APAP处理的大鼠细胞旁[14 C]蔗糖“泄漏”和脑[3 H]可待因蓄积显著增强。此外，claudin-5的定位和蛋白质表达的改变，从大鼠给予500毫克/公斤APAP分离的脑微血管。我们的新的和翻译的数据表明，BBB的完整性改变后，单次高剂量的APAP，结果是相关的患者滥用或误用APAP和/或APAP/阿片类药物组合产品。
The consumption of acetaminophen (APAP) can induce neurological changes in human subjects; however, effects of APAP on blood–brain barrier (BBB) integrity are unknown. BBB changes by APAP can have profound consequences for brain delivery of co-administered drugs. To study APAP effects, female Sprague–Dawley rats (12–16 weeks old) were administered vehicle (i.e., 100% dimethyl sulfoxide (DMSO), intraperitoneally (i.p.)) or APAP (80 mg/kg or 500 mg/kg in DMSO, i.p.; equivalent to a 900 mg or 5600 mg daily dose for a 70 kg human subject). BBB permeability was measured via in situ brain perfusion using [14C]sucrose and [3H]codeine, an opioid analgesic drug that is co-administered with APAP (i.e., Tylenol #3). Localization and protein expression of tight junction proteins (i.e., claudin-5, occludin, ZO-1) were studied in rat brain microvessels using Western blot analysis and confocal microscopy, respectively. Paracellular [14C]sucrose “leak” and brain [3H]codeine accumulation were significantly enhanced in rats treated with 500 mg/kg APAP only. Additionally, claudin-5 localization and protein expression were altered in brain microvessels isolated from rats administered 500 mg/kg APAP. Our novel and translational data show that BBB integrity is altered following a single high APAP dose, results that are relevant to patients abusing or misusing APAP and/or APAP/opioid combination products.
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影响因子：
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作者：
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通讯作者：
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DOI：
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DOI：
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发表时间：
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影响因子：
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作者：
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