2018
DOI: 10.1007/s11095-018-2532-0
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Transport of Pregabalin Via L-Type Amino Acid Transporter 1 (SLC7A5) in Human Brain Capillary Endothelial Cell Line

Abstract: PurposeThe anti-epileptic drug pregabalin crosses the blood-brain barrier (BBB) in spite of its low lipophilicity. This study was performed to determine whether L-type amino acid transporters (LAT1/SLC7A5 and LAT2/SLC7A8) contribute to the uptake of pregabalin.MethodsPregabalin uptake by LATs-transfected HEK293 cells or hCMEC/D3 cells, an in vitro human BBB model, was measured by LC-MS/MS analysis. Expression of LAT1 mRNA in hCMEC/D3 cells was determined by quantitative RT-PCR analysis.ResultsOverexpression of… Show more

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Cited by 50 publications
(29 citation statements)
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“…In addition, the vectorial transport was three-fold higher in the AB direction than in the BA direction ( Figure 6A) and reduced by about 70% in the presence of JPH203, a selective LAT1 inhibitor. This is consistent with the observed 75% inhibition in the uptake of the LAT1 specific substrate pregabalin, after LAT-1 mRNA silencing in the human endothelial cell line hCMEC/D3 [37]. Phenylalanine, another LAT-1 substrate, had a permeability value two-fold higher than in PBEC [2] similar to what was observed for leucine.…”
Section: Drug Transport Studiessupporting
confidence: 88%
“…In addition, the vectorial transport was three-fold higher in the AB direction than in the BA direction ( Figure 6A) and reduced by about 70% in the presence of JPH203, a selective LAT1 inhibitor. This is consistent with the observed 75% inhibition in the uptake of the LAT1 specific substrate pregabalin, after LAT-1 mRNA silencing in the human endothelial cell line hCMEC/D3 [37]. Phenylalanine, another LAT-1 substrate, had a permeability value two-fold higher than in PBEC [2] similar to what was observed for leucine.…”
Section: Drug Transport Studiessupporting
confidence: 88%
“…GBP and PGB are transported into the neuronal cytoplasm via a L-type amino acid transporter ( Su et al, 1995 ). The influx of gabapentinoid drugs was demonstrated to be mediated by LAT1 in brain endothelial cells and in HEK-293 cells stably expressing LAT1 ( Dickens et al, 2013 , Takahashi et al, 2018 ) ( Fig. 2 ).…”
Section: Gabapentinoid Transportmentioning
confidence: 95%
“…In line with this evidence, gabapentin can resemble a L-form of large neutral amino acids ( Su et al, 1995 ), giving it strong structural similarity to endogenous substrates of LAT1 ( Singh and Ecker, 2018 ). On the other hand, short interfering RNA (siRNA) mediated suppression of LAT1 ( Dickens et al, 2013 , Takahashi et al, 2018 ) provided evidence that GBP is transported specifically by this transporter since its uptake was significantly reduced compared to LAT2 targeted siRNA ( Dickens et al, 2013 ). Importantly, BCH inhibits gabapentinoid transport ( Su et al, 2005 , Akanuma et al, 2018 ) and prevents the effect of GBP on HVA Ca 2+ channels ( Hendrich et al, 2008 , Biggs et al, 2014 ).…”
Section: Gabapentinoid Transportmentioning
confidence: 99%
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