In vivo evidence for ATP-dependent and P-glycoprotein-mediated transport of cyclosporin A at the blood-brain barrier

Sakata, Atsushi; Tamai, Ikumi; Kawazu, Kouichi; Deguchi, Yoshiaki; Ohnishi, Toshimasa; Saheki, Akira; Tsuji, Akira

doi:10.1016/0006-2952(94)90601-7

Cited by 133 publications

(51 citation statements)

References 21 publications

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“…Intracellular Rh123 accumulation assay RBMEC were seeded at a density of 5×10 7 /L in 24-well plates. After reaching confluence, cell monolayers were exposed to Rh123 5 µmol/L in serum-free DMEM/F12 medium containing CJX1 and CJX2 at 1, 2.5, 5, and 10 µmol/L at 37 ºC for 90 min, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The capillary endothelial cells protect the brain against many exogenous toxin injuries and sudden fluctuation in the levels of systemic substances. The hydrophobic agents, such as vinblastine and doxorubicin and lipid-soluble compounds, such as cyclosporin A, cannot accumulate in the brain [5][6][7] . P-gp expression in the BBB capillaries is responsible for the extrusion of these compounds from the endothelial cells, and thereby attenuates the accumulation of the drugs in the brain leading to the failure of therapy for the brain disease.…”

Section: Introductionmentioning

confidence: 99%

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Modulation of P-glycoprotein function by amlodipine derivatives in brain microvessel endothelial cells of rats1

Liu

2005

Acta Pharmacologica Sinica

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Aim: To investigate whether the amlodipine derivatives, CJX1 and CJX2, have a modulative effect on P‐glycoprotein (P‐gp) function in rat brain microvessel endothelial cells (RBMEC). Methods: Isolated RBMEC were cultured in DMEM/F12 (1:1) medium. The amount of intracellular rhodamine (Rh123) was determined, using a fluorescence spectrophotometer, to evaluate the function of P‐gp. Results: The accumulation of Rh123 in RBMEC was potentiated in a concentration dependent manner after incubation with CJX1 and CJX2 at 1, 2.5, 5, and 10 μmol/L (P<0.01), but no accumulation of Rh123 was observed in human umbilical vein endothelial cells after incubation with CJX1 and CJX2 10 μmol/L (P>0.05). Accumulation of intracellular Rh123 was increased and efflux of intracellular Rh123 was decreased in a time‐dependent manner from 0–100 min after CJX1 and CXJ2 at 10 μmol/L treatment. The inhibitory effect of CJX1 and CJX2 on P‐gp function was reversible and remained even at 120 min after removal of CJX1 and CJX2 at 2.5 μmol/L from the medium. Conclusion: CJX1 and CJX2 exhibited a potent effect in the inhibition of P‐gp function in vitro.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modulation of P-glycoprotein function by amlodipine derivatives in brain microvessel endothelial cells of rats1

Liu

2005

Acta Pharmacologica Sinica

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“…Knockout of the P-gp gene causes a significant increase in the brain concentration of P-gp substrates. [11][12][13][14] Apart from lipophilic compounds, transporters are involved both in uptake and efflux in the transcellular transport from the brain side to the blood-side. A number of transporter genes have been identified during the last decade, and almost 300 genes have been classified into 43 families of the solute carrier (SLC) family (the list is available from the web site of BIOPARADIGMS URL: http://www.gene.ucl.ac.uk/nomenclature/).…”

Section: Introductionmentioning

confidence: 99%

Active efflux across the blood-brain barrier: Role of the solute carrier family

2005

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Summary: The brain uptake of xenobiotics is restricted by the blood-brain brain barrier formed by brain capillary endothelial cells. Active efflux transport systems in the blood-brain barrier work as a detoxification system in the brain by facilitating removal of xenobiotic compounds from the brain. Drugs, acting in the brain, have to overcome such efflux mechanisms to achieve clinically significant concentration in the brain. Multiple transporters are involved in this efflux transport in the brain capillaries. In the past few years, considerable progress has been made in the cloning of these transporters and their functional characterization after heterologous expression. Members of the solute carrier family (SLC) play an important role in the efflux transport, especially for organic anions, which include organic anion transporting polypeptides (OATP/SLCO) and organic anion transporters (OAT/SLC22A). It is believed that coordination of the members of SLC family, and ABC transporters, such as P-glycoprotein, multidrug resistance protein, and breast cancer-resistant protein (BCRP/ABCG2), allows an efficient vectorial transport across the endothelial cells to remove xenobiotics from the brain. In this review, we shall summarize our current knowledge about their localization, molecular and functional characteristics, and substrate and inhibitor specificity.

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“…In addition, the highest dose of trifluoperazine used (750 pg/kg) is much smaller than its LDS0 (29 mg/kg) for intravenous administration. The transport of cyclosporin A across the bloodbrain barrier is restricted (Sakata et al 1994), however, the administration of 750 pg/kg trifluoperazine one hour prior to 50 mg/kg cyclosporin A injection produced no toxic features. This indicate that even if cyclosporin A distribution to CNS was increased it was not toxic.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin A and Trifluoperazine, Two Resistance‐Modulating Agents, Increase Ivermectin Neurotoxicity in Mice

Marques‐Santos

Bernardo²,

Paula

et al. 1999

Pharmacology & Toxicology

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Ahs/racr: The P-glycoprotein expressed in the blood-brain barrier has been associated with the restricted access of many compounds to the central nervous system. Mice lacking the /ndrla P-glycoprotein gene show an accumulation of various drugs in brain tissues. P-glycoprotein is also correlated with the phenomenon of multidrug resistance in tumour cells. To investigate the effects of drugs that modulate multidrug resistance in the selective permeability of the blood-brain barrier, mice were treated with cyclosporin A or trifluoperazine plus ivermectin, a P-glycoprotein substrate, that has a limited access to the central nervous system. When mice received an injection of cyclosporin A (50 mg/kg. intraperitoneally) or trifluoperazine (750 pg/kg, intraperitoneally) one hour prior to the administration of ivermectin (10-15 mgikg, intraperitoneally) there was an increase in the acute toxicity of ivermectin. HPLC analysis of brain tissues indicated that the ivermectin brain concentration was 2.5 times higher when mice were previously treated with cyclosporin A (50 mg/kg). These results suggest that attention should be given to the side effects of drugs that interact with P-glycoprotein and are commonly used clinically and also to the possibility of creating a pharmacological gap in the blood-brain barrier that allows the access of chemotherapeutic drugs to brain tumours.

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In vivo evidence for ATP-dependent and P-glycoprotein-mediated transport of cyclosporin A at the blood-brain barrier

Cited by 133 publications

References 21 publications

Modulation of P-glycoprotein function by amlodipine derivatives in brain microvessel endothelial cells of rats1

Modulation of P-glycoprotein function by amlodipine derivatives in brain microvessel endothelial cells of rats1

Active efflux across the blood-brain barrier: Role of the solute carrier family

Cyclosporin A and Trifluoperazine, Two Resistance‐Modulating Agents, Increase Ivermectin Neurotoxicity in Mice

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