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Effect of cyclosporin on distribution of methotrexate into the brain of rats.

Ogushi N, Sasaki K, Shimoda M - J. Vet. Med. Sci. (2015)

Bottom Line: 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).If it can, which route is more effective, intravenous or intrathecal?This could be caused by inhibition of P-gp or MRP at the BBB.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

MTX concentrations in the brain (black column) and CSF (white column) at 6 hr postadministration of MTX with or without CysA in rats. Miv group, MTX (i.v.)+saline (i.t.);Mit, MTX (i.t.); Miv+Civ group, MTX (i.v.)+CysA (i.v.)+saline (i.t.); Mit+Civ group, MTX(i.t.)+CysA (i.v.); and Mit+Cit group, MTX (i.t.)+CysA (i.t.). MTX and CysA areabbreviations for methotrexate and cyclosporin A, respectively. Each column and verticalbar show the mean and SD, respectively (n=5). The doses of MTX and CysA were 2 and 0.2mg/body, respectively. *The concentrations of the Mit+Civ and Mit+Cit groups weresignificantly higher than those of the other 3 groups (P<0.05,Scheffe’s multiple comparison test).
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fig_001: MTX concentrations in the brain (black column) and CSF (white column) at 6 hr postadministration of MTX with or without CysA in rats. Miv group, MTX (i.v.)+saline (i.t.);Mit, MTX (i.t.); Miv+Civ group, MTX (i.v.)+CysA (i.v.)+saline (i.t.); Mit+Civ group, MTX(i.t.)+CysA (i.v.); and Mit+Cit group, MTX (i.t.)+CysA (i.t.). MTX and CysA areabbreviations for methotrexate and cyclosporin A, respectively. Each column and verticalbar show the mean and SD, respectively (n=5). The doses of MTX and CysA were 2 and 0.2mg/body, respectively. *The concentrations of the Mit+Civ and Mit+Cit groups weresignificantly higher than those of the other 3 groups (P<0.05,Scheffe’s multiple comparison test).

Mentions: Each group’s MTX concentrations in the brain and CSF are shown in Fig. 1Fig. 1.


Effect of cyclosporin on distribution of methotrexate into the brain of rats.

Ogushi N, Sasaki K, Shimoda M - J. Vet. Med. Sci. (2015)

MTX concentrations in the brain (black column) and CSF (white column) at 6 hr postadministration of MTX with or without CysA in rats. Miv group, MTX (i.v.)+saline (i.t.);Mit, MTX (i.t.); Miv+Civ group, MTX (i.v.)+CysA (i.v.)+saline (i.t.); Mit+Civ group, MTX(i.t.)+CysA (i.v.); and Mit+Cit group, MTX (i.t.)+CysA (i.t.). MTX and CysA areabbreviations for methotrexate and cyclosporin A, respectively. Each column and verticalbar show the mean and SD, respectively (n=5). The doses of MTX and CysA were 2 and 0.2mg/body, respectively. *The concentrations of the Mit+Civ and Mit+Cit groups weresignificantly higher than those of the other 3 groups (P<0.05,Scheffe’s multiple comparison test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591162&req=5

fig_001: MTX concentrations in the brain (black column) and CSF (white column) at 6 hr postadministration of MTX with or without CysA in rats. Miv group, MTX (i.v.)+saline (i.t.);Mit, MTX (i.t.); Miv+Civ group, MTX (i.v.)+CysA (i.v.)+saline (i.t.); Mit+Civ group, MTX(i.t.)+CysA (i.v.); and Mit+Cit group, MTX (i.t.)+CysA (i.t.). MTX and CysA areabbreviations for methotrexate and cyclosporin A, respectively. Each column and verticalbar show the mean and SD, respectively (n=5). The doses of MTX and CysA were 2 and 0.2mg/body, respectively. *The concentrations of the Mit+Civ and Mit+Cit groups weresignificantly higher than those of the other 3 groups (P<0.05,Scheffe’s multiple comparison test).
Mentions: Each group’s MTX concentrations in the brain and CSF are shown in Fig. 1Fig. 1.

Bottom Line: 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).If it can, which route is more effective, intravenous or intrathecal?This could be caused by inhibition of P-gp or MRP at the BBB.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan.

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.

No MeSH data available.


Related in: MedlinePlus