Participation of Monocarboxylate Transporter 8, But Not P-Glycoprotein, in Carrier-Mediated Cerebral Elimination of Phenytoin across the Blood-Brain Barrier.
Participation of Monocarboxylate Transporter 8, But Not P-Glycoprotein, in Carrier-Mediated Cerebral Elimination of Phenytoin across the Blood-Brain Barrier.
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DOI：
10.1007/s11095-021-03003-1
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发表时间：
2021-01
影响因子：
3.7
通讯作者：
Hosoya KI
中科院分区：
文献类型：
--
作者：
Jomura R;Akanuma SI;Bauer B;Yoshida Y;Kubo Y;Hosoya KI
在这项研究中，我们详细研究了苯妥英钠通过血脑屏障（BBB）的转运，以确定参与血脑屏障介导的苯妥英钠从脑中流出的转运蛋白。我们通过测定脑外排指数（BEI）和脑切片摄取来评价苯妥英钠在体内的脑-血外排转运。我们还进行了脑灌注实验和BEI研究P-糖蛋白（P-gp）缺陷小鼠。此外，我们确定了mRNA表达的单羧酸转运蛋白（MCT）在分离的脑毛细血管和进行苯妥英钠摄取研究MCT表达非洲爪蟾卵母细胞。[14 C]苯妥英脑外排具有时间依赖性，大鼠和小鼠的半衰期分别为17 min和31 min。脑内预给药未标记的苯妥英会减弱BBB介导的苯妥英外排转运，表明载体介导的苯妥英外排转运通过BBB。在大鼠中预先给予P-gp底物和在小鼠中遗传性P-gp缺乏不影响BBB介导的苯妥英外排转运。相比之下，预先给予MCT 8抑制剂可减弱苯妥英外排。此外，大鼠MCT 8表达爪蟾卵母细胞表现出[14 C]苯妥英摄取，这是由未标记的苯妥英抑制。我们的数据表明，血脑屏障中的MCT 8参与苯妥英从大脑到血液的外排转运。
In this study, we investigated in detail the transport of phenytoin across the blood-brain barrier (BBB) to identify the transporter(s) involved in BBB-mediated phenytoin efflux from the brain. We evaluated the brain-to-blood efflux transport of phenytoin in vivo by determining the brain efflux index (BEI) and uptake in brain slices. We additionally conducted brain perfusion experiments and BEI studies in P-glycoprotein (P-gp)-deficient mice. In addition, we determined the mRNA expression of monocarboxylate transporter (MCT) in isolated brain capillaries and performed phenytoin uptake studies in MCT-expressing Xenopus oocytes. [14C]Phenytoin brain efflux was time-dependent with a half-life of 17 min in rats and 31 min in mice. Intracerebral pre-administration of unlabeled phenytoin attenuated BBB-mediated phenytoin efflux transport, suggesting carrier-mediated phenytoin efflux transport across the BBB. Pre-administration of P-gp substrates in rats and genetic P-gp deficiency in mice did not affect BBB-mediated phenytoin efflux transport. In contrast, pre-administration of MCT8 inhibitors attenuated phenytoin efflux. Moreover, rat MCT8-expressing Xenopus oocytes exhibited [14C]phenytoin uptake, which was inhibited by unlabeled phenytoin. Our data suggest that MCT8 at the BBB participates in phenytoin efflux transport from the brain to the blood.
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影响因子：
6.3
作者：
CORNFORD, EM;PARDRIDGE, WM;OLDENDORF, WH
通讯作者：
OLDENDORF, WH
影响因子：
2.6
作者：
Fohner, Alison E.;Ranatunga, Dilrini K.;Schaefer, Catherine A.
通讯作者：
Schaefer, Catherine A.
影响因子：
2.5
作者：
Ramasamy, Kesavan;Narayan, Sunil K.;Chandrasekaran, Adithan
通讯作者：
Chandrasekaran, Adithan
影响因子：
1.6
作者：
Miyake, Zenshi;Ishii, Kazuhiro;Tamaoka, Akira
通讯作者：
Tamaoka, Akira
影响因子：
3.6
作者：
Cui, YH;König, J;Keppler, D
通讯作者：
Keppler, D