Involvement of Multidrug Resistance-Associated Protein 4 in Efflux Transport of Prostaglandin E2 across Mouse Blood-Brain Barrier and Its Inhibition by Intravenous Administration of Cephalosporins
Involvement of Multidrug Resistance-Associated Protein 4 in Efflux Transport of Prostaglandin E2 across Mouse Blood-Brain Barrier and Its Inhibition by Intravenous Administration of Cephalosporins
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DOI：
10.1124/jpet.109.165332
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发表时间：
2010-06-01
影响因子：
3.5
通讯作者：
Ohtsuki, Sumio
中科院分区：
文献类型：
--
作者：
Akanuma, Shin-ichi;Hosoya, Ken-ichi;Ohtsuki, Sumio
前列腺素E-2（PGE（2））是大脑中突触信号和兴奋性的调节剂。由于PGE（2）在成人脑中几乎不被酶失活，因此其脑水平被认为是通过跨血脑屏障（BBB）的外排转运来控制的。本研究的目的是阐明PGE（2）在血脑屏障的外排转运以及各种药物与这一过程的相互作用。[H-3]PGE（2）通过BBB从脑中消除，半衰期为16.3 min，3 mM未标记PGE（2）可抑制消除。多药耐药相关蛋白4（MRP 4/ABCC 4）定位于血脑屏障的管腔膜。表达MRP 4的膜囊泡显示出对[H-3]PGE（2）的显著摄取，头孢美唑可抑制该摄取，IC 50值为10.2 μ M。在浓度为20 μ M时，包括头孢唑啉、头孢噻肟、头孢曲松和酮洛芬在内的几种药物显著抑制[H-3]PGE（2）摄取到表达MRP 4的膜囊泡中。使用脑外排指数法，发现预先给予头孢美唑、头孢唑林、头孢曲松和头孢噻肟可抑制[H-3]PGE（2）从脑中流出通过BBB。此外，静脉注射头孢美唑剂量依赖性地减少[H-3]PGE（2）通过BBB的消除（ID 50 = 120 mg/kg）。这些结果表明，PGE（2）通过MRP 4介导的BBB外排转运从脑中消除，外周给予头孢美唑可降低PGE（2）在BBB的外排转运;这种相互作用可能影响脑功能。
Prostaglandin E-2 (PGE(2)) acts as a modulator of synaptic signaling and excitability in the brain. Because PGE(2) is barely inactivated enzymatically in adult brain, its brain level is considered to be controlled by efflux transport across the blood-brain barrier (BBB). The purpose of the present study was to clarify the efflux transport of PGE(2) at the BBB and the interaction of various drugs with this process. [H-3]PGE(2) was eliminated from brain across the BBB with a half-life of 16.3 min, and the elimination was inhibited by 3 mM unlabeled PGE(2). Multidrug resistance-associated protein 4 (MRP4/ABCC4) was reported to be localized at the luminal membrane of the BBB. MRP4-expressing membrane vesicles showed significant uptake of [H-3]PGE(2) and the uptake was inhibited by cefmetazole with an IC50 value of 10.2 mu M. At the concentration of 20 mu M, several drugs, including cefazolin, cefotaxime, ceftriaxone, and ketoprofen, significantly inhibited [H-3]PGE(2) uptake into MRP4-expressing membrane vesicles. Using the brain efflux index method, preadministration of cefmetazole, cefazolin, ceftriaxone, and cefotaxime was found to inhibit [H-3]PGE(2) efflux from brain across the BBB. Furthermore, intravenous administration of the cefmetazole dose dependently reduced [H-3]PGE(2) elimination across the BBB (ID50 = 120 mg/kg). These results indicate that PGE(2) is eliminated from the brain by MRP4-mediated efflux transport at the BBB, and peripheral administration of cefmetazole decreases the efflux transport of PGE(2) at the BBB; this interaction may influence brain function.