Blood-brain barrier damage and brain penetration of antiepileptic drugs: role of serum proteins and brain edema.
Blood-brain barrier damage and brain penetration of antiepileptic drugs: role of serum proteins and brain edema.
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DOI：
10.1111/j.1528-1167.2008.01989.x
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发表时间：
2009-04
期刊：
影响因子：
5.6
通讯作者：
Janigro D
中科院分区：
文献类型：
--
作者：
Marchi N;Betto G;Fazio V;Fan Q;Ghosh C;Machado A;Janigro D
血脑屏障（BBB）通透性增加是放射学检测耐药癫痫病变的影响区域。抗癫痫药物（AEDs）的脑渗透可能受到BBB损伤的影响。我们研究了BBB损伤对亲水性[脱氧葡萄糖（DOG）和蔗糖]和亲脂性（苯妥英和地西泮）分子脑分布的影响。我们检验了亲脂性和亲水性药物分布受血脑屏障损伤不同影响的假设。通过颈动脉内注射高渗甘露醇在大鼠体内造成血脑屏障破坏（BBBD）。测量药物（H3-蔗糖、3 H-脱氧葡萄糖、14 C-苯妥英和C14-地西泮）或未标记的苯妥英，并将其与脑含水量和蛋白质外渗相关联。在体外海马脑片暴露于不同的渗透压，药物渗透和水含量进行了评估，分别通过分析和光密度法。BBBD导致血清蛋白和放射性标记药物外渗，但与脑水无显著变化相关。体外脑切片中含水量的大变化对药物渗透的影响很小。在这两种情况下，总的药物渗透性增加亲脂性比亲水性化合物。BBBD减少了脑中游离苯妥英的量。BBBD后，药物与蛋白质的结合是总脑药物蓄积的主要控制器。渗透性BBBD增加血清蛋白外渗并降低游离苯妥英脑水平。这些结果强调了脑环境和血脑屏障完整性在确定药物向脑分布中的重要性。如果在耐药模型中得到证实，这些机制可能有助于药物在难治性癫痫中的脑分布。
Increased blood–brain barrier (BBB) permeability is radiologically detectable in regions affected by drug-resistant epileptogenic lesions. Brain penetration of antiepileptic drugs (AEDs) may be affected by BBB damage. We studied the effects of BBB damage on brain distribution of hydrophilic [deoxy-glucose (DOG) and sucrose] and lipophilic (phenytoin and diazepam) molecules. We tested the hypothesis that lipophilic and hydrophilic drug distribution is differentially affected by BBB damage. In vivo BBB disruption (BBBD) was performed in rats by intracarotid injection of hyperosmotic mannitol. Drugs (H3-sucrose, 3H-deoxy-glucose, 14C-phenytoin, and C14-diazepam) or unlabeled phenytoin was measured and correlated to brain water content and protein extravasation. In vitro hippocampal slices were exposed to different osmolarities; drug penetration and water content were assessed by analytic and densitometric methods, respectively. BBBD resulted in extravasation of serum protein and radiolabeled drugs, but was associated with no significant change in brain water. Large shifts in water content in brain slices in vitro caused a small effect on drug penetration. In both cases, total drug permeability increase was greater for lipophilic than hydrophilic compounds. BBBD reduced the amount of free phenytoin in the brain. After BBBD, drug binding to protein is the main controller of total brain drug accumulation. Osmotic BBBD increased serum protein extravasation and reduced free phenytoin brain levels. These results underlie the importance of brain environment and BBB integrity in determining drug distribution to the brain. If confirmed in drug-resistant models, these mechanisms could contribute to drug brain distribution in refractory epilepsies.
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影响因子：
6.2
作者：
DIETZEL, I;HEINEMANN, U;LUX, HD
通讯作者：
LUX, HD
影响因子：
2.9
作者：
Kaya, Mehmet;Gurses, Candan;Kemikler, Gonul
通讯作者：
Kemikler, Gonul
影响因子：
4.8
作者：
NEUWELT, EA;BALABAN, E;FRENKEL, E
通讯作者：
FRENKEL, E
影响因子：
6.3
作者：
CORNFORD, EM;PARDRIDGE, WM;OLDENDORF, WH
通讯作者：
OLDENDORF, WH
影响因子：
5.6
作者：
Diehl, B;Najm, I;Lüders, HO
通讯作者：
Lüders, HO