title: Effect of cyclosporin on distribution of methotrexate into the brain of rats.
abstract: The effect of the antitumor drug, methotrexate (MTX), which is applied to brain tumors, is restricted by the blood-brain barrier (BBB), which is composed of P-glycoprotein (P-gp) and multidrug resistance associated protein (MRP). We, therefore, studied if a potent P-gp and MRP modulator, cyclosporin A (CysA), can modulate the MTX concentration in the rat brain. If it can, which route is more effective, intravenous or intrathecal? We intravenously or intrathecally administered MTX to rats with or without CysA. After 6 hr, brains and cerebrospinal fluid (CSF) were sampled, and their MTX concentrations were compared. Each MTX concentration was determined by high-performance liquid chromatography with UV detection. CysA had no significant affect on the MTX concentration in the brain or CSF when MTX was intravenously injected. In contrast, when MTX was intrathecally administered, CysA had a larger effect on the MTX concentration in the brain than in the CSF. This indicates CysA potentiated the brain MTX concentration when MTX was intrathecally administered. It is suggested that CysA did not potentiate the distribution of MTX from blood into the brain, but instead potentiated the distribution of MTX from CSF into the brain. Since chemicals in CSF generally diffuse into the brain easily, CysA probably inhibited the excretion of MTX from the brain. This could be caused by inhibition of P-gp or MRP at the BBB. Therefore, CysA can be a useful tool to achieve an appropriate MTX concentration in brain.
authors.affiliation: Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Ogushi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Sasaki
authors.forename: Minoru
authors.initials: M
authors.lastname: Shimoda
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis* / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000494:pharmacology*; D007275:Injections, Intravenous; D007278:Injections, Spinal; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000032:analysis* / Q000493:pharmacokinetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D016572:Cyclosporine; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins