Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Pharm Res
2022 Jul 01;397:1549-1559. doi: 10.1007/s11095-022-03223-z.
Show Gene links
Show Anatomy links
Characterization of Aripiprazole Uptake Transporter in the Blood-Brain Barrier Model hCMEC/D3 Cells by Targeted siRNA Screening.
Kadoguchi M
,
Arakawa H
,
Honda R
,
Hotta K
,
Shirasaka Y
,
Deguchi Y
,
Tamai I
.
???displayArticle.abstract???
AIM: Identification of blood-brain barrier (BBB) uptake transporters is a major challenge in the research and development of central nervous system (CNS) drugs. However, conventional methods that consider known drug uptake characteristics have failed at identifying the responsible transporter molecule. The present study aimed at identifying aripiprazole uptake transporters in BBB model hCMEC/D3 cells using a knockdown screening study targeting various transporters, including uncharacterized ones.
METHODS: We evaluated the effect of 214 types of siRNA targeting transporters on the uptake of aripiprazole, an atypical antipsychotic drug, in hCMEC/D3 cells. Aripiprazole uptake was determined using Xenopus oocytes expressing the candidate genes extracted from the siRNA screening assay.
RESULTS: The estimated unbound brain to plasma concentration ratio (Kp,uu,brain) of aripiprazole was estimated as 0.67 in wild-type mice and 1.94 in abcb1a/1b/abcg2 knockout mice, suggesting the involvement of both uptake and efflux transporters in BBB permeation. According to siRNA knockdown screening studies, organic cation/carnitine transporter 2 (OCTN2) and long-chain fatty acid transporter 1 (FATP1) were identified as candidate genes. The uptake of aripiprazole by hCMEC/D3 cells was decreased by OCTN2 inhibitors, but not by FATP1 inhibitors. A partially increased uptake of aripiprazole was observed in OCTN2-expressing Xenopus oocytes. Finally, to evaluate transporter-mediated BBB permeation of drugs, the reported and estimated Kp,uu,brain values were summarized.
CONCLUSIONS: A knockdown screening study in combination with Kp,uu,brain values showed that aripiprazole was a potential substrate of OCTN2. The technique described in this study can be applied to identifying novel BBB transporters for CNS drugs.
Abbott,
Structure and function of the blood-brain barrier.
2010, Pubmed
Abbott,
Structure and function of the blood-brain barrier.
2010,
Pubmed
André,
Clonidine transport at the mouse blood-brain barrier by a new H+ antiporter that interacts with addictive drugs.
2009,
Pubmed
Anraku,
Glycaemic control boosts glucosylated nanocarrier crossing the BBB into the brain.
2017,
Pubmed
Arakawa,
Renal Reabsorptive Transport of Uric Acid Precursor Xanthine by URAT1 and GLUT9.
2020,
Pubmed
,
Xenbase
Bundgaard,
Species comparison of in vivo P-glycoprotein-mediated brain efflux using mdr1a-deficient rats and mice.
2012,
Pubmed
Chen,
P-glycoprotein limits the brain penetration of nonsedating but not sedating H1-antagonists.
2003,
Pubmed
Choo,
Role of P-glycoprotein on the brain penetration and brain pharmacodynamic activity of the MEK inhibitor cobimetinib.
2014,
Pubmed
Choo,
Preclinical disposition of GDC-0973 and prospective and retrospective analysis of human dose and efficacy predictions.
2012,
Pubmed
Doran,
The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model.
2005,
Pubmed
Fridén,
In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids.
2007,
Pubmed
Geier,
Profiling solute carrier transporters in the human blood-brain barrier.
2013,
Pubmed
Hendrikse,
Complete in vivo reversal of P-glycoprotein pump function in the blood-brain barrier visualized with positron emission tomography.
1998,
Pubmed
Higuchi,
Memantine transport by a proton-coupled organic cation antiporter in hCMEC/D3 cells, an in vitro human blood-brain barrier model.
2015,
Pubmed
Hiranaka,
Design, Synthesis, and Blood-Brain Barrier Transport Study of Pyrilamine Derivatives as Histone Deacetylase Inhibitors.
2018,
Pubmed
Huang,
Differential role of P-glycoprotein and breast cancer resistance protein in drug distribution into brain, CSF and peripheral nerve tissues in rats.
2015,
Pubmed
Inano,
Acetyl-L-carnitine permeability across the blood-brain barrier and involvement of carnitine transporter OCTN2.
2003,
Pubmed
Ishiguro,
Influx and efflux transport of H1-antagonist epinastine across the blood-brain barrier.
2004,
Pubmed
Kageyama,
The 4F2hc/LAT1 complex transports L-DOPA across the blood-brain barrier.
2000,
Pubmed
Kalvass,
Use of plasma and brain unbound fractions to assess the extent of brain distribution of 34 drugs: comparison of unbound concentration ratios to in vivo p-glycoprotein efflux ratios.
2007,
Pubmed
Kano,
Carnitine/organic cation transporter OCTN2 (Slc22a5) is responsible for renal secretion of cephaloridine in mice.
2009,
Pubmed
,
Xenbase
Kemper,
The influence of the P-glycoprotein inhibitor zosuquidar trihydrochloride (LY335979) on the brain penetration of paclitaxel in mice.
2004,
Pubmed
Kido,
Molecular and functional identification of large neutral amino acid transporters LAT1 and LAT2 and their pharmacological relevance at the blood-brain barrier.
2001,
Pubmed
Kido,
Functional relevance of carnitine transporter OCTN2 to brain distribution of L-carnitine and acetyl-L-carnitine across the blood-brain barrier.
2001,
Pubmed
Kim,
The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors.
1998,
Pubmed
Kitamura,
Cocktail-Dosing Microdialysis Study to Simultaneously Assess Delivery of Multiple Organic-Cationic Drugs to the Brain.
2016,
Pubmed
Kurosawa,
Involvement of Proton-Coupled Organic Cation Antiporter in Varenicline Transport at Blood-Brain Barrier of Rats and in Human Brain Capillary Endothelial Cells.
2017,
Pubmed
Laramy,
Pharmacokinetic Assessment of Cooperative Efflux of the Multitargeted Kinase Inhibitor Ponatinib Across the Blood-Brain Barrier.
2018,
Pubmed
Liu,
Progress in brain penetration evaluation in drug discovery and development.
2008,
Pubmed
Liu,
Drug Distribution into Peripheral Nerve.
2018,
Pubmed
Maurer,
Relationship between exposure and nonspecific binding of thirty-three central nervous system drugs in mice.
2005,
Pubmed
Miecz,
Localization of organic cation/carnitine transporter (OCTN2) in cells forming the blood-brain barrier.
2008,
Pubmed
Mochizuki,
Functional Investigation of Solute Carrier Family 35, Member F2, in Three Cellular Models of the Primate Blood-Brain Barrier.
2021,
Pubmed
Mueckler,
Facilitative glucose transporters.
1994,
Pubmed
Nagasaka,
Impact of genetic deficiencies of P-glycoprotein and breast cancer resistance protein on pharmacokinetics of aripiprazole and dehydroaripiprazole.
2014,
Pubmed
Nagaya,
Utility of cerebrospinal fluid drug concentration as a surrogate for unbound brain concentration in nonhuman primates.
2014,
Pubmed
Ochiai,
The blood-brain barrier fatty acid transport protein 1 (FATP1/SLC27A1) supplies docosahexaenoic acid to the brain, and insulin facilitates transport.
2017,
Pubmed
Ohashi,
Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance.
1999,
Pubmed
Ohashi,
Molecular and physiological evidence for multifunctionality of carnitine/organic cation transporter OCTN2.
2001,
Pubmed
Ohashi,
Studies on functional sites of organic cation/carnitine transporter OCTN2 (SLC22A5) using a Ser467Cys mutant protein.
2002,
Pubmed
Ohtsuki,
Quantitative targeted absolute proteomic analysis of transporters, receptors and junction proteins for validation of human cerebral microvascular endothelial cell line hCMEC/D3 as a human blood-brain barrier model.
2013,
Pubmed
Okura,
Involvement of the pyrilamine transporter, a putative organic cation transporter, in blood-brain barrier transport of oxycodone.
2008,
Pubmed
Okura,
Blood-brain barrier transport of pramipexole, a dopamine D2 agonist.
2007,
Pubmed
Okura,
Proton-coupled organic cation antiporter-mediated uptake of apomorphine enantiomers in human brain capillary endothelial cell line hCMEC/D3.
2014,
Pubmed
Raub,
Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft.
2015,
Pubmed
Sadiq,
Diphenhydramine active uptake at the blood-brain barrier and its interaction with oxycodone in vitro and in vivo.
2011,
Pubmed
Sadiq,
Validation of a P-Glycoprotein (P-gp) Humanized Mouse Model by Integrating Selective Absolute Quantification of Human MDR1, Mouse Mdr1a and Mdr1b Protein Expressions with In Vivo Functional Analysis for Blood-Brain Barrier Transport.
2015,
Pubmed
Shimomura,
Functional expression of a proton-coupled organic cation (H+/OC) antiporter in human brain capillary endothelial cell line hCMEC/D3, a human blood-brain barrier model.
2013,
Pubmed
Shirasaka,
Effect of P-glycoprotein expression levels on the concentration-dependent permeability of drugs to the cell membrane.
2008,
Pubmed
Summerfield,
Examining the Uptake of Central Nervous System Drugs and Candidates across the Blood-Brain Barrier.
2016,
Pubmed
Tamai,
Transporter-mediated permeation of drugs across the blood-brain barrier.
2000,
Pubmed
Tamai,
Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2.
1998,
Pubmed
Tsuji,
Carrier-mediated or specialized transport of drugs across the blood-brain barrier.
1999,
Pubmed
Uchida,
Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors.
2011,
Pubmed
Uchida,
Blood-brain barrier (BBB) pharmacoproteomics: reconstruction of in vivo brain distribution of 11 P-glycoprotein substrates based on the BBB transporter protein concentration, in vitro intrinsic transport activity, and unbound fraction in plasma and brain in mice.
2011,
Pubmed
Wagner,
Functional and pharmacological characterization of human Na(+)-carnitine cotransporter hOCTN2.
2000,
Pubmed
,
Xenbase
Weksler,
Blood-brain barrier-specific properties of a human adult brain endothelial cell line.
2005,
Pubmed
Yamazaki,
Carrier-mediated transport of H1-antagonist at the blood-brain barrier: mepyramine uptake into bovine brain capillary endothelial cells in primary monolayer cultures.
1994,
Pubmed