CAN a P-gp modulator assist in the control of methotrexate concentrations in the rat brain? -inhibitory effects of rhodamine 123, a specific substrate for P-gp, on methotrexate excretion from the rat brain and its optimal route of administration.
CAN a P-gp modulator assist in the control of methotrexate concentrations in the rat brain? -inhibitory effects of rhodamine 123, a specific substrate for P-gp, on methotrexate excretion from the rat brain and its optimal route of administration.
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DOI：
10.1292/jvms.16-0315
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发表时间：
2017-02-14
期刊：
影响因子：
--
通讯作者：
Shimoda M
中科院分区：
文献类型：
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作者：
Ogushi N;Sasaki K;Shimoda M
虽然甲氨蝶呤（MTX）主要通过还原型叶酸载体转运，但P-gp和MRP 1也可能参与其转运。在我们以前的研究中，一种有效的P-gp和MRP 1调节剂，环孢霉素A，增强MTX在大鼠脑中的浓度。由于它是重要的MTX治疗脑肿瘤，以澄清转运蛋白是占主导地位的，我们在此确定是否特定的P-gp底物，罗丹明123（Rho 123），加强运输和保留MTX在大脑中。注射MTX后立即静脉或鞘内注射Rho 123。MTX注射后6或12小时，在脑脊液（CSF）取样后立即分离脑。还间歇性采集血液。MTX浓度测定血浆，脑脊液和脑使用高效液相色谱法与紫外检测。静脉注射MTX时，Rho 123不影响脑内MTX浓度。然而，Rho 123导致MTX鞘内注射后12小时脑内MTX浓度显著升高。这表明Rho 123抑制MTX从脑中的排泄，但不增强其从血液到脑中的分布。提示P-gp可能是MTX在大鼠脑内的主要转运体之一。因此，P-gp调节剂治疗可能有助于脑肿瘤的鞘内MTX治疗。由于MTX的血药浓度-时间曲线不受Rho 123的影响，因此P-gp调节剂治疗可能不会增强MTX的不良反应。
Although methotrexate (MTX) is mainly transported by reduced folate carrier, P-gp and MRP1 may also be involved in its transport. In our previous study, a potent P-gp and MRP1 modulator, Cyclosporine A, potentiated MTX concentration in rat brain. Since it is important for MTX therapy for brain tumor to clarify which transporter is dominant, we herein determined whether the specific P-gp substrate, rhodamine123 (Rho123), potentiates the transport and retention of MTX in the brain. Rho123 was injected intravenously or intrathecally into rats immediately after injection of MTX. 6 or 12 hr after the MTX injection, brains were isolated just after the sampling of cerebrospinal fluid (CSF). Blood was also collected intermittently. MTX concentrations were determined in plasma, CSF and the brain using high-performance liquid chromatography with UV detection. When MTX was intravenously injected, Rho123 didn’t affect MTX concentrations in the brain. However, Rho123 resulted in significantly higher MTX concentrations in the brain at 12 hr after injection when MTX was intrathecally injected. It is suggested that Rho123 inhibits the excretion of MTX from the brain, but does not potentiate its distribution from the blood into the brain. This reveals that P-gp can be one of the major transporters of MTX in rat brain. Therefore, treatments with P-gp modulators may contribute to intrathecal MTX therapy for brain tumor. Since plasma concentration-time curves of MTX were not affected by Rho123, treatments with P-gp modulators may not potentiate the adverse effects of MTX.