Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter, P-glycoprotein

Tsuji, Akira; Tamai, Ikumi; Sakata, Atsushi; Tenda, Yoshiyuki; Terasaki, Tetsuya

doi:10.1016/0006-2952(93)90677-o

Cited by 145 publications

(59 citation statements)

References 17 publications

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“…However, transport polarity and its physiological significance are difficult to study by in vivo techniques. Primary cultured monolayers of bovine BCECs offer the advantage for studies of the transendothelial transport of various substances [15][16][17][18]. Furthermore, it is expected that the monolayers of BCECs remains polarized because several membrane functions have been reported to localize in the manner that is consistent with the brain capillary endothelial cells in vivo [8,12,19,20].…”

Section: Introductionmentioning

confidence: 99%

Brain‐to‐blood active transport of β‐alanine across the blood–brain barrier

et al. 1997

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A high-affinity antiluminal uptake system for ß-alanine was demonstrated in primary cultured bovine brain capillary endothelial cells (BCEC) for which K, is 66.9 μΜ. β-alanine uptake was energy-, sodium-and chloride ion-dependent. ß-amino acids strongly inhibited the uptake, while a-and γ-amino acids had a little or no inhibitory effect. In ATP-depleted cells, the uptake was stimulated by preloading ß-alanine or taurine but not by L-leucine. These results suggest that ß-alanine is actively transported across the antiluminal membrane of BCECs that is common to ß-amino acids. The system may function for the efflux from the brain to blood.

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Section: Introductionmentioning

confidence: 99%

Brain‐to‐blood active transport of β‐alanine across the blood–brain barrier

et al. 1997

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“…Rhodamine 123 is a fluorescent dye commonly used for the determination of P-glycoprotein function in vivo and in vitro (2,(12)(13)(14). Cyclosporin A is a known substrate for the P-glycoprotein efflux system in vivo and in vitro (3,5,14). In Figure 1 the effect of cyclosporin A on rhodamine 123 uptake in BMECs is shown.…”

Section: Resultsmentioning

confidence: 99%

“…Both cyclosporin A and verapamil were shown to increase the uptake of rhodamine 123, a fluorescent marker of the Pglycoprotein efflux system (2,(12)(13)(14). Cyclosporin A and verapamil are known inhibitors of the P-glycoprotein efflux system that are commonly used to distinguish the existence of this efflux system on cells (2,3,5,13,14). Our results compare favorably, in a qualitative manner, with the studies of Wang et al (14) who showed about a 3-fold enhancement of rhodamine 123 uptake Rose Despite being relatively lipophilic, ivermectin typically achieves its lowest concentrations in the brain (11).…”

Section: Discussionmentioning

confidence: 99%

“…P-glycoprotein is believed to function as an energy-dependent efflux pump and is often overexpressed in cancer cells (1). P-glycoprotein is also expressed in noncancerous tissues including the endothelial cells of the blood-brain barrier (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, the efflux system has been shown to be present and functional in the membranes of cultured murine (2,4), porcine (2), and bovine brain capillary endothelial cells (5). The bloodbrain barrier has many unique characteristics which restrict the exchange of molecules between the systemic circulation and the extracellular fluid compartment of the brain.…”

Section: Introductionmentioning

confidence: 99%

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Rose

Peckham

Scism

et al. 1998

Neurochemical Research

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Evaluation of the role of P-glycoprotein in ivermectin uptake by primary cultures of bovine brain microvessel endothelial cells. Neurochem. Res. 23,[203][204][205][206][207][208][209] Keywords: brain microvessel endothelia; blood-brain barrier; P-glycoprotein; rhodamine 123; ivermectin Abstract: The P-glycoprotein efflux system located on the apical membrane of brain capillary endothelial cells functions as part of the blood-brain barrier. In this study, primary cultures of bovine brain microvessel endothelial cells (BMECs) were investigated for the presence of a Pglycoprotein system and its contribution in regulating ivermectin distribution across the bloodbrain barrier. Results of rhodamine 123 uptake studies with cyclosporin A and verapamil as substrates indicated that a functional efflux system was present on BMECs. Immunoblot analysis with the C219 monoclonal antibody to the product of the multidrug resistant member 1(MDR1) gene also confirmed the expression of MDR1 in the BMECs. Unbound ivermectin was shown to significantly increase the uptake of rhodamine 123 in BMECs, however, the drug only modestly enhanced the transcellular passage of rhodamine. The results of these studies affirmed that unbound ivermectin is an inhibitor of the MDR1 efflux system in BMECs. Text of paper:Rose, J.M., Peckham, S.L., Scism, J.L., and Audus, K.L. (1998) Evaluation of the role of P-glycoprotein in ivermectin uptake by primary cultures of bovine brain microvessel endothelial cells. Neurochem. Res. 23,[203][204][205][206][207][208][209]

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Chemical Delivery Systems

Bodor

Buchwald

2012

Retrometabolic Drug Design and Targeting

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Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter, P-glycoprotein

Cited by 145 publications

References 17 publications

Brain‐to‐blood active transport of β‐alanine across the blood–brain barrier

Brain‐to‐blood active transport of β‐alanine across the blood–brain barrier

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