Limited distribution of new quinolone antibacterial agents into brain caused by multiple efflux transporters at the blood-brain barrier.
Limited distribution of new quinolone antibacterial agents into brain caused by multiple efflux transporters at the blood-brain barrier.
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由于血脑屏障处的多个外排转运蛋白导致新的喹诺酮抗菌剂有限地分布到大脑中。
DOI：
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发表时间：
2000
影响因子：
3.5
通讯作者：
Akira Tsuji
中科院分区：
文献类型：
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作者：
Ikumi Tamai;Junko Yamashita;Yasuto Kido;A. Ohnari;Y. Sai;Yuichiro Shima;K. Naruhashi;Shoichi Koizumi;Akira Tsuji
用永生化的大鼠脑毛细血管内皮细胞RBEC 1体外研究了新型喹诺酮类抗菌药物在血脑屏障（BBB）上的转运，用大鼠和多药耐药mdr 1a/1b基因缺陷小鼠脑灌注法研究了体内喹诺酮类抗菌药物在血脑屏障上的转运。通过脑灌注测量的格雷帕沙星的渗透系数增加过量的未标记的格雷帕沙星，表明饱和的BBB外排系统的参与。在未标记的喹诺酮类药物存在的情况下，稳态时RBEC 1细胞对[（14）C]格帕沙星、[（14）C]司帕沙星和[（14）C]左氧氟沙星的吸收系数增加。在各种喹诺酮类药物存在下，[（14）C]格帕沙星的稳态摄取增加。在mdr 1a/1b基因缺陷小鼠中，[（14）C]格帕沙星和[（14）C]司帕沙星的脑分布（根据脑/血浆游离浓度比进行评价）显著高于野生型小鼠，表明P-糖蛋白作为外排转运蛋白参与其中。阴离子化合物，包括4，4 '-二异硫氰酸基芪-2，2'-二磺酸（DIDS）和染料木素，增加RBEC 1细胞对[（14）C]格帕沙星的稳态摄取。由于[（14）C]格帕沙星在多药耐药相关蛋白（MRP）1过表达细胞中由MRP转运，并且由于RBEC 1和原代培养的脑毛细血管内皮细胞表达MRP 1，因此该蛋白可能是喹诺酮类药物的额外外排转运蛋白。此外，[（14）C]格帕沙星通过BBB的渗透系数增加DIDS或在脑灌注方法中的碳酸氢根离子的情况下。DIDS或碳酸氢根离子不影响MRP 1功能。因此，喹诺酮类药物的脑分布受到多种外排转运蛋白（包括P-糖蛋白、MRP 1和未知阴离子交换转运蛋白）作用的限制。
Transport of new quinolone antibacterial agents (quinolones) at the blood-brain barrier (BBB) was studied in vitro by using immortalized rat brain capillary endothelial cells RBEC1, and in vivo by using the brain perfusion method in rats and multidrug-resistant mdr1a/1b gene-deficient mice. The permeability coefficient of grepafloxacin measured by brain perfusion was increased by an excess of unlabeled grepafloxacin, suggesting a participation of a saturable BBB efflux system. Uptake coefficients of [(14)C]grepafloxacin, [(14)C]sparfloxacin, and [(14)C]levofloxacin by RBEC1 cells at the steady state were increased in the presence of the unlabeled quinolones. The steady-state uptake of [(14)C]grepafloxacin was increased in the presence of various quinolones. Brain distributions of [(14)C]grepafloxacin and [(14)C]sparfloxacin evaluated in terms of the brain-to-plasma free concentration ratio in mdr1a/1b gene-deficient mice were significantly higher than those in wild-type mice, demonstrating an involvement of P-glycoprotein as the efflux transporter. Anionic compounds, including 4, 4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) and genistein, increased the steady-state uptake of [(14)C]grepafloxacin by RBEC1 cells. Because [(14)C]grepafloxacin was transported by multidrug resistance-associated protein (MRP), in MRP1-overexpressing cells and because RBEC1 and primary cultured brain capillary endothelial cells expressed MRP1, this protein may be an additional efflux transporter for quinolones. Furthermore, the permeability coefficient of [(14)C]grepafloxacin across the BBB was increased by DIDS or in the absence of bicarbonate ions in the brain perfusion method. DIDS or bicarbonate ion did not affect MRP1 function. Accordingly, the brain distribution of quinolones is restricted by the action of multiple efflux transporters, including P-glycoprotein, MRP1, and an unknown anion exchange transporter.