{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T15:18:31Z","timestamp":1790781511098,"version":"4.1.0"},"reference-count":81,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T00:00:00Z","timestamp":1682640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS#117906"],"award-info":[{"award-number":["R01 NS#117906"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Our lab previously established that metformin, a first-line type two diabetes treatment, activates the Nrf2 pathway and improves post-stroke recovery. Metformin\u2019s brain permeability value and potential interaction with blood\u2013brain barrier (BBB) uptake and efflux transporters are currently unknown. Metformin has been shown to be a substrate of organic cationic transporters (Octs) in the liver and kidneys. Brain endothelial cells at the BBB have been shown to express Octs; thus, we hypothesize that metformin uses Octs for its transport across the BBB. We used a co-culture model of brain endothelial cells and primary astrocytes as an in vitro BBB model to conduct permeability studies during normoxia and hypoxia using oxygen\u2013glucose deprivation (OGD) conditions. Metformin was quantified using a highly sensitive LC-MS\/MS method. We further checked Octs protein expression using Western blot analysis. Lastly, we completed a plasma glycoprotein (P-GP) efflux assay. Our results showed that metformin is a highly permeable molecule, uses Oct1 for its transport, and does not interact with P-GP. During OGD, we found alterations in Oct1 expression and increased permeability for metformin. Additionally, we showed that selective transport is a key determinant of metformin\u2019s permeability during OGD, thus, providing a novel target for improving ischemic drug delivery.<\/jats:p>","DOI":"10.3390\/pharmaceutics15051357","type":"journal-article","created":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T05:46:06Z","timestamp":1682660766000},"page":"1357","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Permeability of Metformin across an In Vitro Blood\u2013Brain Barrier Model during Normoxia and Oxygen-Glucose Deprivation Conditions: Role of Organic Cation Transporters (Octs)"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5923-2613","authenticated-orcid":false,"given":"Sejal","family":"Sharma","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"},{"name":"Center for Blood-Brain Barrier Research, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"},{"name":"Center for Blood-Brain Barrier Research, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khondker Ayesha","family":"Akter","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"},{"name":"Center for Blood-Brain Barrier Research, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeideh","family":"Nozohouri","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"},{"name":"Center for Blood-Brain Barrier Research, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina Rahman","family":"Archie","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"},{"name":"Center for Blood-Brain Barrier Research, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6959-3487","authenticated-orcid":false,"given":"Dhavalkumar","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"},{"name":"Center for Blood-Brain Barrier Research, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Villalba","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"},{"name":"Center for Blood-Brain Barrier Research, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Abbruscato","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"},{"name":"Center for Blood-Brain Barrier Research, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1758-5996-5-6","article-title":"Metformin: An old but still the best treatment for type 2 diabetes","volume":"5","author":"Rojas","year":"2013","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"482","DOI":"10.5603\/EP.2017.0050","article-title":"Metformin\u2014A new old drug","volume":"68","author":"Marek","year":"2017","journal-title":"Endokrynol. Pol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3389\/fendo.2020.00191","article-title":"Metformin and its benefits for various diseases","volume":"11","author":"Lv","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"400","DOI":"10.3389\/fendo.2018.00400","article-title":"The therapeutic potential of metformin in neurodegenerative diseases","volume":"9","author":"Rotermund","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1007\/s11095-017-2199-y","article-title":"Metformin\u2013A future therapy for neurodegenerative diseases: Theme: Drug discovery, development and delivery in Alzheimer\u2019s disease Guest Editor: Davide Brambilla","volume":"34","author":"Sikora","year":"2017","journal-title":"Pharm. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.neures.2019.12.017","article-title":"Neuroprotective effect of metformin on dopaminergic neurodegeneration and \u03b1-synuclein aggregation in C. elegans model of Parkinson\u2019s disease","volume":"162","author":"Saewanee","year":"2021","journal-title":"Neurosci. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"119343","DOI":"10.1016\/j.lfs.2021.119343","article-title":"Repurposing metformin to treat age-related neurodegenerative disorders and ischemic stroke","volume":"274","author":"Sharma","year":"2021","journal-title":"Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.redox.2017.06.006","article-title":"Offsetting the impact of smoking and e-cigarette vaping on the cerebrovascular system and stroke injury: Is Metformin a viable countermeasure?","volume":"13","author":"Kaisar","year":"2017","journal-title":"Redox Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s12987-021-00261-4","article-title":"Comparative assessment of in vitro BBB tight junction integrity following exposure to cigarette smoke and e-cigarette vapor: A quantitative evaluation of the protective effects of metformin using small-molecular-weight paracellular markers","volume":"18","author":"Kadry","year":"2021","journal-title":"Fluids Barriers CNS"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.drudis.2020.01.007","article-title":"Novel approaches for the delivery of therapeutics in ischemic stroke","volume":"25","author":"Nozohouri","year":"2020","journal-title":"Drug Discov. Today"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"C2","DOI":"10.1152\/ajpcell.00187.2018","article-title":"Neurovascular unit transport responses to ischemia and common coexisting conditions: Smoking and diabetes","volume":"316","author":"Sifat","year":"2019","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"75","DOI":"10.2147\/VHRM.S39213","article-title":"Current perspectives on the use of intravenous recombinant tissue plasminogen activator (tPA) for treatment of acute ischemic stroke","volume":"10","author":"Johnston","year":"2014","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_13","first-page":"e334","article-title":"Response by mistry et al to letter regarding article, \u201cmechanical thrombectomy outcomes with and without intravenous thrombolysis in stroke patients: A meta-analysis\u201d","volume":"48","author":"Mistry","year":"2017","journal-title":"Stroke"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.3390\/ijms23031898","article-title":"Blood\u2013Brain Barrier Transporters: Opportunities for Therapeutic Development in Ischemic Stroke","volume":"23","author":"Nilles","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/s41386-020-0752-6","article-title":"Signature-based approaches for informed drug repurposing: Targeting CNS disorders","volume":"46","author":"Shukla","year":"2020","journal-title":"Neuropsychopharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1186\/s12974-022-02487-x","article-title":"Reduced microglia activation following metformin administration or microglia ablation is sufficient to prevent functional deficits in a mouse model of neonatal stroke","volume":"19","author":"Bourget","year":"2022","journal-title":"J. Neuroinflamm."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zemgulyte, G., Tanaka, S., Hide, I., Sakai, N., Pampuscenko, K., Borutaite, V., and Rastenyte, D. (2021). Evaluation of the effectiveness of post-stroke metformin treatment using permanent middle cerebral artery occlusion in rats. Pharmaceuticals, 14.","DOI":"10.3390\/ph14040312"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jns.2019.03.015","article-title":"The progress of neuronal autophagy in cerebral ischemia stroke: Mechanisms, roles and research methods","volume":"400","author":"Hou","year":"2019","journal-title":"J. Neurol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.redox.2017.02.007","article-title":"Role of Nrf2 and protective effects of Metformin against tobacco smoke-induced cerebrovascular toxicity","volume":"12","author":"Prasad","year":"2017","journal-title":"Redox Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1023\/B:PHAM.0000026423.48583.e2","article-title":"Correction of permeability with pore radius of tight junctions in Caco-2 monolayers improves the prediction of the dose fraction of hydrophilic drugs absorbed by humans","volume":"21","author":"Saitoh","year":"2004","journal-title":"Pharm. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/bdd.755","article-title":"Mechanisms for membrane transport of metformin in human intestinal epithelial Caco-2 cells","volume":"32","author":"Horie","year":"2011","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.neuro.2022.02.002","article-title":"Biological determinants impact the neurovascular toxicity of nicotine and tobacco smoke: A pharmacokinetic and pharmacodynamics perspective","volume":"89","author":"Archie","year":"2022","journal-title":"Neurotoxicology"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Barthels, D., Prateeksha, P., Nozohouri, S., Villalba, H., Zhang, Y., Sharma, S., Anderson, S., Howlader, S.I., Nambiar, A., and Abbruscato, T.J. (2022). Dental Pulp-Derived Stem Cells Preserve Astrocyte Health during Induced Gliosis by Modulating Mitochondrial Activity and Functions. Cell. Mol. Neurobiol., 1\u201323.","DOI":"10.1007\/s10571-022-01291-8"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s12987-022-00339-7","article-title":"Potential role of astrocyte angiotensin converting enzyme 2 in the neural transmission of COVID-19 and a neuroinflammatory state induced by smoking and vaping","volume":"19","author":"Zhang","year":"2022","journal-title":"Fluids Barriers CNS"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12987-022-00371-7","article-title":"Short-term exposure to JUUL electronic cigarettes can worsen ischemic stroke outcome","volume":"19","author":"Sifat","year":"2022","journal-title":"Fluids Barriers CNS"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"886099","DOI":"10.3389\/fddev.2022.886099","article-title":"Effects of Nicotine Exposure From Tobacco Products and Electronic Cigarettes on the Pathogenesis of Neurological Diseases: Impact on CNS Drug Delivery","volume":"2","author":"Sharma","year":"2022","journal-title":"Front. Drug Deliv."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1177\/0271678X18798162","article-title":"A new era for stroke therapy: Integrating neurovascular protection with optimal reperfusion","volume":"38","author":"Shi","year":"2018","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Hacker, K., Maas, R., Kornhuber, J., Fromm, M.F., and Zolk, O. (2015). Substrate-dependent inhibition of the human organic cation transporter OCT2: A comparison of metformin with experimental substrates. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0136451"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s11095-022-03179-0","article-title":"Differences in Cerebral Distribution between Imipramine and Paroxetine via Membrane Transporters at the Rat Blood-Brain Barrier","volume":"39","author":"Akanuma","year":"2022","journal-title":"Pharm. Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gebauer, L., Rafehi, M., and Brockm\u00f6ller, J. (2022). Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3. Biomolecules, 12.","DOI":"10.3390\/biom12101507"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6714","DOI":"10.1038\/s41467-022-34284-8","article-title":"Structural basis of organic cation transporter-3 inhibition","volume":"13","author":"Khanppnavar","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1002\/hep.510290530","article-title":"Cloning and functional expression of a mouse liver organic cation transporter","volume":"29","author":"Green","year":"1999","journal-title":"Hepatology"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Za\u00efr, Z.M., Eloranta, J.J., Stieger, B., and Kullak-Ublick, G.A. (2008). Pharmacogenetics of OATP (SLC21\/SLCO), OAT and OCT (SLC22) and PEPT (SLC15) Transporters in the Intestine, Liver and Kidney, Future Medicine Ltd.","DOI":"10.2217\/14622416.9.5.597"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Albekairi, T.H., Vaidya, B., Patel, R., Nozohouri, S., Villalba, H., Zhang, Y., Lee, Y.S., Al-Ahmad, A., and Abbruscato, T.J. (2019). Brain delivery of a potent opioid receptor agonist, biphalin during ischemic stroke: Role of organic anion transporting polypeptide (OATP). Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11090467"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Ronaldson, P.T., Brzica, H., Abdullahi, W., Reilly, B.G., and Davis, T.P. (2020). Transport Properties of Statins by OATP1A2 and Regulation by Transforming Growth Factor-\u03b2 (TGF-\u03b2) Signaling in Human Endothelial Cells. J. Pharmacol. Exp. Ther.","DOI":"10.1124\/jpet.120.000267"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"114181","DOI":"10.1016\/j.expneurol.2022.114181","article-title":"Targeting organic cation transporters at the blood-brain barrier to treat ischemic stroke in rats","volume":"357","author":"Stanton","year":"2022","journal-title":"Exp. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/bdd.371","article-title":"Acetyl-L-carnitine permeability across the blood-brain barrier and involvement of carnitine transporter OCTN2","volume":"24","author":"Inano","year":"2003","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1517\/17460441.3.6.677","article-title":"Strategies to assess blood\u2013brain barrier penetration","volume":"3","author":"Di","year":"2008","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s11307-012-0556-0","article-title":"P-glycoprotein function at the blood\u2013brain barrier: Effects of age and gender","volume":"14","author":"Lubberink","year":"2012","journal-title":"Mol. Imaging Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.2174\/1381612043384844","article-title":"ABC Transporters and the blood-brain barrier","volume":"10","author":"Begley","year":"2004","journal-title":"Curr. Pharm. Des."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1002\/jcb.22375","article-title":"Purity, cell viability, expression of GFAP and bystin in astrocytes cultured by different procedures","volume":"109","author":"Du","year":"2009","journal-title":"J. Cell. Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Nozohouri, S., Noorani, B., Al-Ahmad, A., and Abbruscato, T.J. (2023, April 25). Estimating Brain permeability using in vitro blood-brain barrier models. In Permeability Barrier: Methods and Protocols; Methods in Molecular Biology; 2020; pp. 47\u201372. Available online: https:\/\/link.springer.com\/protocol\/10.1007\/7651_2020_311.","DOI":"10.1007\/7651_2020_311"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1124\/jpet.121.000831","article-title":"Glutamate buffering capacity and blood-brain barrier protection of opioid receptor agonists biphalin and nociceptin","volume":"379","author":"Nozohouri","year":"2021","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2015.03.022","article-title":"In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment","volume":"1609","author":"Yang","year":"2015","journal-title":"Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"115309","DOI":"10.1016\/j.ejmech.2023.115309","article-title":"Studies on diketopiperazine and dipeptide analogs as opioid receptor ligands","volume":"254","author":"Nia","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1021\/acschemneuro.6b00029","article-title":"Central nervous system multiparameter optimization desirability: Application in drug discovery","volume":"7","author":"Wager","year":"2016","journal-title":"ACS Chem. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"12705","DOI":"10.1021\/acs.jmedchem.1c00759","article-title":"Discovery of first-in-class peptidomimetic neurolysin activators possessing enhanced brain penetration and stability","volume":"64","author":"Rahman","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s11095-004-1193-3","article-title":"Metformin transport by renal basolateral organic cation transporter hOCT2","volume":"22","author":"Kimura","year":"2005","journal-title":"Pharm. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1124\/dmd.104.002220","article-title":"Saturable distribution of tacrine into the striatal extracellular fluid of the rat: Evidence of involvement of multiple organic cation transporters in the transport","volume":"33","author":"Sung","year":"2004","journal-title":"Drug Metab. Dispos."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Sekhar, G.N., Georgian, A.R., Sanderson, L., Vizcay-Barrena, G., Brown, R.C., Muresan, P., Fleck, R.A., and Thomas, S.A. (2017). Organic cation transporter 1 (OCT1) is involved in pentamidine transport at the human and mouse blood-brain barrier (BBB). PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0173474"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1002\/hep.23103","article-title":"Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver","volume":"50","author":"Nies","year":"2009","journal-title":"Hepatology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"379","DOI":"10.2133\/dmpk.20.379","article-title":"Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1","volume":"20","author":"Kimura","year":"2005","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1124\/jpet.114.220350","article-title":"Four cation-selective transporters contribute to apical uptake and accumulation of metformin in Caco-2 cell monolayers","volume":"352","author":"Han","year":"2015","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1007\/s11095-007-9254-z","article-title":"Polyspecific organic cation transporters: Structure, function, physiological roles, and biopharmaceutical implications","volume":"24","author":"Koepsell","year":"2007","journal-title":"Pharm. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1124\/dmd.120.000170","article-title":"Differences in metformin and thiamine uptake between human and mouse organic cation transporter 1: Structural determinants and potential consequences for intrahepatic concentrations","volume":"48","author":"Meyer","year":"2020","journal-title":"Drug Metab. Dispos."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1080\/17425255.2021.1915284","article-title":"Update on drug-drug interaction at organic cation transporters: Mechanisms, clinical impact, and proposal for advanced in vitro testing","volume":"17","author":"Koepsell","year":"2021","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1124\/jpet.116.232660","article-title":"Molecular properties of drugs interacting with SLC22 transporters OAT1, OAT3, OCT1, and OCT2: A machine-learning approach","volume":"359","author":"Liu","year":"2016","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S0168-0102(02)00120-7","article-title":"Localization of norepinephrine and serotonin transporter in mouse brain capillary endothelial cells","volume":"44","author":"Wakayama","year":"2002","journal-title":"Neurosci. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1111\/jnc.13363","article-title":"Effects of lipopolysaccharide on the expression of plasma membrane monoamine transporter (PMAT) at the blood-brain barrier and its implications to the transport of neurotoxins","volume":"135","author":"Wu","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12987-019-0158-1","article-title":"Region-specific blood\u2013brain barrier transporter changes leads to increased sensitivity to amisulpride in Alzheimer\u2019s disease","volume":"16","author":"Sekhar","year":"2019","journal-title":"Fluids Barriers CNS"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1208\/s12248-017-0091-7","article-title":"Blood-brain barrier protection as a therapeutic strategy for acute ischemic stroke","volume":"19","author":"Sifat","year":"2017","journal-title":"AAPS J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/j.jep.2011.08.063","article-title":"Baicalin reduces the permeability of the blood\u2013brain barrier during hypoxia in vitro by increasing the expression of tight junction proteins in brain microvascular endothelial cells","volume":"141","author":"Zhu","year":"2012","journal-title":"J. Ethnopharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.2353\/ajpath.2007.060693","article-title":"Hypoxia disrupts the barrier function of neural blood vessels through changes in the expression of claudin-5 in endothelial cells","volume":"170","author":"Koto","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3390\/pharmaceutics12020154","article-title":"Transporter-mediated delivery of small molecule drugs to the brain: A critical mechanism that can advance therapeutic development for ischemic stroke","volume":"12","author":"Williams","year":"2020","journal-title":"Pharmaceutics"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.1016\/j.xphs.2017.04.032","article-title":"Involvement of proton-coupled organic cation antiporter in varenicline transport at blood-brain barrier of rats and in human brain capillary endothelial cells","volume":"106","author":"Kurosawa","year":"2017","journal-title":"J. Pharm. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1111\/j.1471-4159.2010.06801.x","article-title":"Cellular localization of the organic cation transporters, OCT1 and OCT2, in brain microvessel endothelial cells and its implication for MPTP transport across the blood-brain barrier and MPTP-induced dopaminergic toxicity in rodents","volume":"114","author":"Lin","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s12264-013-1298-y","article-title":"Progesterone treatment before experimental hypoxia-ischemia enhances the expression of glucose transporter proteins GLUT1 and GLUT3 in neonatal rats","volume":"29","author":"Li","year":"2013","journal-title":"Neurosci. Bull."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"605398","DOI":"10.3389\/fphys.2020.605398","article-title":"Blood-brain barrier damage in ischemic stroke and its regulation by endothelial mechanotransduction","volume":"11","author":"Nian","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12987-016-0040-3","article-title":"Fluid and ion transfer across the blood\u2013brain and blood\u2013cerebrospinal fluid barriers; a comparative account of mechanisms and roles","volume":"13","author":"Hladky","year":"2016","journal-title":"Fluids Barriers CNS"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s11011-010-9180-3","article-title":"The Na\u2013K\u2013Cl co-transporter in astrocyte swelling","volume":"25","author":"Jayakumar","year":"2010","journal-title":"Metab. Brain Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.bcp.2006.03.016","article-title":"Alterations in transporter expression in liver, kidney, and duodenum after targeted disruption of the transcription factor HNF1\u03b1","volume":"72","author":"Maher","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"644126","DOI":"10.3389\/fncel.2021.644126","article-title":"Ion channels and electrophysiological properties of astrocytes: Implications for emergent stimulation technologies","volume":"15","author":"McNeill","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Koepsell, H. (2023, March 14). General overview of organic cation transporters in brain. In Organic Cation Transporters in the Central Nervous System; Handbook of Experimental Pharmacology; 2021; pp. 1\u201339. Available online: https:\/\/link.springer.com\/chapter\/10.1007\/164_2021_449.","DOI":"10.1007\/164_2021_449"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1002\/glia.22484","article-title":"Molecular mechanism of histamine clearance by primary human astrocytes","volume":"61","author":"Yoshikawa","year":"2013","journal-title":"Glia"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0169-409X(98)00085-4","article-title":"P-Glycoprotein, a gatekeeper in the blood\u2013brain barrier","volume":"36","author":"Schinkel","year":"1999","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/clpt.2013.81","article-title":"In vitro methods to support transporter evaluation in drug discovery and development","volume":"94","author":"Brouwer","year":"2013","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1124\/jpet.102.039255","article-title":"Passive permeability and p-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs","volume":"303","author":"Doan","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.ijpharm.2004.10.007","article-title":"Evaluation of the MDR-MDCK cell line as a permeability screen for the blood\u2013brain barrier","volume":"288","author":"Wang","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1124\/jpet.105.092916","article-title":"Improving the in vitro prediction of in vivo central nervous system penetration: Integrating permeability, p-glycoprotein efflux, and free fractions in blood and brain","volume":"316","author":"Summerfield","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1021\/acs.molpharmaceut.8b01143","article-title":"Development of simplified in vitro P-glycoprotein substrate assay and in silico prediction models to evaluate transport potential of P-glycoprotein","volume":"16","author":"Ohashi","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1007\/s11095-022-03218-w","article-title":"In-Vivo and ex-vivo brain uptake studies of peptidomimetic neurolysin activators in healthy and stroke animals","volume":"39","author":"Nozohouri","year":"2022","journal-title":"Pharm. Res."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/5\/1357\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:25:36Z","timestamp":1760124336000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/5\/1357"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,28]]},"references-count":81,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["pharmaceutics15051357"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15051357","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,28]]}}}