Involvement of the Pyrilamine Transporter, a Putative Organic Cation Transporter, in Blood-Brain Barrier Transport of Oxycodone

2008 ◽  
Vol 36 (10) ◽  
pp. 2005-2013 ◽  
Author(s):  
Takashi Okura ◽  
Asami Hattori ◽  
Yusuke Takano ◽  
Takenori Sato ◽  
Margareta Hammarlund-Udenaes ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Organic Cation ◽  
Organic Cation Transporter ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Organic cation transporter 1 (OCT1) is involved in pentamidine transport at the human and mouse blood-brain barrier (BBB)

PLoS ONE ◽  
2017 ◽  
Vol 12 (3) ◽  
pp. e0173474 ◽  
Author(s):  
Gayathri N. Sekhar ◽  
Ana R. Georgian ◽  
Lisa Sanderson ◽  
Gema Vizcay-Barrena ◽  
Rachel C. Brown ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Organic Cation ◽  
Organic Cation Transporter ◽  
Brain Barrier ◽  
Mouse Blood ◽  
Blood Brain ◽  
Organic Cation Transporter 1 ◽  
Human And Mouse

scholarly journals Region-specific blood-brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer’s disease

2019 ◽  
Author(s):  
Gayathri Nair Sekhar ◽  
Alice L. Fleckney ◽  
Sevda Tomova Boyanova ◽  
Huzefa Rupawala ◽  
Rachel Lo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Organic Cation ◽  
Brain Barrier ◽  
Organic Cation Transporters ◽  
Blood Brain ◽  
Function Expression ◽  
Increased Sensitivity ◽  
Solute Carrier

AbstractResearch into amisulpride use in Alzheimer’s disease (AD) implicates blood-brain barrier (BBB) dysfunction in antipsychotic sensitivity. Solute carrier function in AD has not been widely studied. This study tests the hypothesis that organic cation transporters contribute to the BBB delivery of antipsychotics and is disrupted in AD.In vitroBBB studies indicated that [3H]amisulpride and [3H]haloperidol were transported by OCT1. Amisulpride also utilized PMAT. Molecular docking predicted that amisulpride and haloperidol are OCT1, PMAT and MATE1 substrates, and amisulpride is not a P-gp substrate. Amisulpride brain uptake increased in 3xTgAD compared to wildtype mice. PMAT and MATE1 expression was reduced in brain from AD patients compared to controls. The increased sensitivity of Alzheimer’s patients to amisulpride is related to previously unreported changes in OCT1, PMAT and MATE1 function/expression at the BBB. Dose adjustments may be required for drugs that are substrates of these transporters when prescribing for AD patients.

scholarly journals An Interspecies Molecular and Functional Study of Organic Cation Transporters at the Blood-Brain Barrier: From Rodents to Humans

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 308 ◽  
Author(s):  
Catarina Chaves ◽  
Federica Campanelli ◽  
Hélène Chapy ◽  
David Gomez-Zepeda ◽  
Fabienne Glacial ◽  
...  
Keyword(s):  
Human Brain ◽  
Blood Brain Barrier ◽  
Organic Cation ◽  
Brain Barrier ◽  
Organic Cation Transporters ◽  
Qrt Pcr ◽  
Brain Microvessels ◽  
Blood Brain ◽  
Cation Transporters ◽  
The Brain

Organic cation transporters (OCTs) participate in the handling of compounds in kidneys and at the synaptic cleft. Their role at the blood-brain barrier (BBB) in brain drug delivery is still unclear. The presence of OCT1,2,3 (SLC22A1-3) in mouse, rat and human isolated brain microvessels was investigated by either qRT-PCR, quantitative proteomics and/or functional studies. BBB transport of the prototypical substrate [3H]-1-methyl-4-phenylpyridinium ([3H]-MPP+) was measured by in situ brain perfusion in six mouse strains and in Sprague Dawley rats, in primary human brain microvascular endothelial cells seeded on inserts, in the presence or absence of OCTs and a MATE1 (SLC49A1) inhibitor. The results show negligible OCT1 (SLC22A1) and OCT2 (SLC22A2) expression in either mice, rat or human brain microvessels, while OCT3 expression was identified in rat microvessels by qRT-PCR. The in vitro human cellular uptake of [3H]-MPP+ was not modified by OCTs/MATE-inhibitor. Brain transport of [3H]-MPP+ remains unchanged between 2- and 6-month old mice, and no alteration was observed in mice and rats with inhibitors. In conclusion, the evidenced lack of expression and/or functional OCTs and MATE at the BBB allows the maintenance of the brain homeostasis and function as it prevents an easy access of their neurotoxicant substrates to the brain parenchyma.

Localization of organic cation/carnitine transporter (OCTN2) in cells forming the blood–brain barrier

2007 ◽  
Vol 0 (0) ◽  
pp. 071108171001002-??? ◽  
Author(s):  
Dorota Miecz ◽  
Elżbieta Januszewicz ◽  
Magdalena Czeredys ◽  
Barry T. Hinton ◽  
Vincent Berezowski ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Organic Cation ◽  
Brain Barrier ◽  
Carnitine Transporter ◽  
Blood Brain ◽  
In Cells

Organic Cation Transporters are Involved in Fluoxetine Transport Across the Blood-Brain Barrier in Vivo and in Vitro

2021 ◽  
Vol 18 ◽  
Author(s):  
Min Wang ◽  
Yingying Sun ◽  
Bingying Hu ◽  
Zhisheng He ◽  
Shanshan Chen ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Cellular Uptake ◽  
Organic Cation ◽  
Brain Barrier ◽  
Organic Cation Transporters ◽  
Cellular Accumulation ◽  
Blood Brain ◽  
The Brain

Background : The research and development of drugs for the treatment of central nervous system diseases faces many challenges at present. One of the most important questions to be answered is, how does the drug cross the blood-brain barrier to get to the target site for pharmacological action. Fluoxetine is widely used in clinical antidepressant therapy. However, the mechanism by which fluoxetine passes through the BBB also remains unclear. Under physiological pH conditions, fluoxetine is an organic cation with a relatively small molecular weight (<500), which is in line with the substrate characteristics of organic cation transporters (OCTs). Therefore, this study aimed to investigate the interaction of fluoxetine with OCTs at the BBB and BBB-associated efflux transporters. This is of great significance for fluoxetine to better treat depression. Moreover, it can provide a theoretical basis for clinical drug combinations. Methods: In vitro BBB model was developed using human brain microvascular endothelial cells (hCMEC/D3), and the cellular accumulation was tested in the presence or absence of transporter inhibitors. In addition, an in vivo trial was performed in rats to investigate the effect of OCTs on the distribution of fluoxetine in the brain tissue. Fluoxetine concentration was determined by a validated UPLC-MS/MS method. Results: The results showed that amantadine (an OCT1/2 inhibitor) and prazosin (an OCT1/3 inhibitor) significantly decreased the cellular accumulation of fluoxetine (P <.001). Moreover, we found that N-methylnicotinamide (an OCT2 inhibitor) significantly inhibited the cellular uptake of 100 and 500 ng/mL fluoxetine (P <.01 and P <.05 respectively). In contrast, corticosterone (an OCT3 inhibitor) only significantly inhibited the cellular uptake of 1000 ng/mL fluoxetine (P <.05). The P-glycoprotein (P-gp) inhibitor, verapamil, and the multidrug resistance resistance-associated proteins (MRPs) inhibitor, MK571, significantly decreased the cellular uptake of fluoxetine. However, intracellular accumulation of fluoxetine was not significantly changed when fluoxetine was incubated with the breast cancer resistance protein (BCRP) inhibitor Ko143. Furthermore, in vivo experiments proved that corticosterone and prazosin significantly inhibited the brain-plasma ratio of fluoxetine at 5.5 h and 12 h, respectively. Conclusion: OCTs might play a significant role in the transport of fluoxetine across the BBB. In addition, P-gp, BCRP, and MRPs seemed not to mediate the efflux transport of fluoxetine.

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