CAN a P-gp modulator assist in the control of methotrexate concentrations inthe rat brain? −inhibitory effects of rhodamine 123, a specific substrate for P-gp, onmethotrexate excretion from the rat brain and its optimal route ofadministration

The Journal of Veterinary Medical Science

Kazuaki SASAKI¹  Naofumi OGUSHI²  Minoru SHIMODA² 

[1] Ogushi Animal Hospital, 3-2556-5 Wakasa Tokorozawa-shi,Saitama 359-1151, Japan;The Department of Veterinary Medicine, Faculty ofAgriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509,Japan

关键词: blood-brain barrier;    intrathecal administration;    methotrexate;    p-glycoprotein;    rhodamine 123;   

DOI  :  10.1292/jvms.16-0315

学科分类：兽医学

来源: Japanese Society of Veterinary Science

【 摘 要 】

Although methotrexate (MTX) is mainly transported by reduced folate carrier, P-gp andMRP1 may also be involved in its transport. In our previous study, a potent P-gp and MRP1modulator, Cyclosporine A, potentiated MTX concentration in rat brain. Since it isimportant for MTX therapy for brain tumor to clarify which transporter is dominant, weherein determined whether the specific P-gp substrate, rhodamine123 (Rho123), potentiatesthe transport and retention of MTX in the brain. Rho123 was injected intravenously orintrathecally into rats immediately after injection of MTX. 6 or 12 hr after the MTXinjection, brains were isolated just after the sampling of cerebrospinal fluid (CSF).Blood was also collected intermittently. MTX concentrations were determined in plasma, CSFand the brain using high-performance liquid chromatography with UV detection. When MTX wasintravenously injected, Rho123 didn’t affect MTX concentrations in the brain. However,Rho123 resulted in significantly higher MTX concentrations in the brain at 12 hr afterinjection when MTX was intrathecally injected. It is suggested that Rho123 inhibits theexcretion of MTX from the brain, but does not potentiate its distribution from the bloodinto the brain. This reveals that P-gp can be one of the major transporters of MTX in ratbrain. Therefore, treatments with P-gp modulators may contribute to intrathecal MTXtherapy for brain tumor. Since plasma concentration-time curves of MTX were not affectedby Rho123, treatments with P-gp modulators may not potentiate the adverse effects ofMTX.

【 授权许可】

Unknown