Membrane transporters have a crucial role in compounds' brain drug delivery. They allow not only the penetration of a wide variety of different compounds to cross the endothelial cells of the blood-brain barrier (BBB), but also the accumulation of them into the brain parenchymal cells. Solute carriers (SLCs), with nearly 500 family members, are the largest group of membrane transporters. Unfortunately, not all SLCs are fully characterized and used in rational drug design. However, if the structural features for transporter interactions (binding and translocation) are known, a prodrug approach can be utilized to temporarily change the pharmacokinetics and brain delivery properties of almost any compound. In this review, main transporter subtypes that are participating in brain drug disposition or have been used to improve brain drug delivery across the BBB via the prodrug approach, are introduced. Moreover, the ability of selected transporters to be utilized in intrabrain drug delivery is discussed. Thus, this comprehensive review will give insights into the methods, such as computational drug design, that should be utilized more effectively to understand the detailed transport mechanisms. Moreover, factors, such as transporter expression modulation pathways in diseases that should be taken into account in rational (pro)drug development, are considered to achieve successful clinical applications in the future.

Department of Pharmaceutical Chemistry Drug Analysis and Radiopharmacy Medical University of Lodz ul Muszyńskiego 1 90 151 Lodz Poland

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo Namesti 542 2 160 00 Prague Czech Republic

School of Pharmacy Faculty of Health Sciences University of Eastern Finland P O Box 1627 FI 70211 Kuopio Finland

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Deuschl G., Beghi E., Fazekas F., Varga T., Christoforidi A.K., Sipido E., Bassetti C.L., Vos T., Feigin V.L. The burden of neurological diseases in Europe: An analysis for the Global Burden of Disease Study 2017. Lancet Public Health. 2020;5:e551–e567. doi: 10.1016/S2468-2667(20)30190-0. PubMed DOI

Olesen J., Gustavsson A., Svensson M., Wittchen H.-U., Jönsson B. The economic cost of brain disorders in Europe. Eur. J. Neurol. 2012;19:155–162. doi: 10.1111/j.1468-1331.2011.03590.x. PubMed DOI

Pankevich D.E., Altevogt B.M., Dunlop J., Gage F.H., Hyman S.E. Improving and Accelerating Drug Development for Nervous System Disorders. Neuron. 2014;84:546–553. doi: 10.1016/j.neuron.2014.10.007. PubMed DOI PMC

Gribkoff V.K., Kaczmarek L.K. The need for new approaches in CNS drug discovery: Why drugs have failed, and what can be done to improve outcomes. Neuropharmacology. 2016;120:11–19. doi: 10.1016/j.neuropharm.2016.03.021. PubMed DOI PMC

Uchida Y., Yagi Y., Takao M., Tano M., Umetsu M., Hirano S., Usui T., Tachikawa M., Terasaki T. Comparison of Absolute Protein Abundances of Transporters and Receptors among Blood–Brain Barriers at Different Cerebral Regions and the Blood–Spinal Cord Barrier in Humans and Rats. Mol. Pharm. 2020;17:2006–2020. doi: 10.1021/acs.molpharmaceut.0c00178. PubMed DOI

Pardridge W.M. Drug Transport across the Blood–Brain Barrier. J. Cereb. Blood Flow Metab. 2012;32:1959–1972. doi: 10.1038/jcbfm.2012.126. PubMed DOI PMC

Dragunow M. The adult human brain in preclinical drug development. Nat. Rev. Drug Discov. 2008;7:659–666. doi: 10.1038/nrd2617. PubMed DOI

Lee G., Dallas S., Hong M., Bendayan R. Drug transporters in the central nervous system: Brain barriers and brain parenchyma considerations. Pharmacol. Rev. 2001;53:569–596. doi: 10.1146/annurev.pharmtox.41.1.569. PubMed DOI

Banks W.A. From blood–brain barrier to blood–brain interface: New opportunities for CNS drug delivery. Nat. Rev. Drug Discov. 2016;15:275–292. doi: 10.1038/nrd.2015.21. PubMed DOI

Lin L., Yee S.W., Kim R.B., Giacomini K.M. SLC transporters as therapeutic targets: Emerging opportunities. Nat. Rev. Drug Discov. 2015;14:543–560. doi: 10.1038/nrd4626. PubMed DOI PMC

Huttunen K.M., Raunio H., Rautio J. Prodrugs—From Serendipity to Rational Design. Pharmacol. Rev. 2011;63:750–771. doi: 10.1124/pr.110.003459. PubMed DOI

Rautio J., Meanwell N., Di L., Hageman M.J. The expanding role of prodrugs in contemporary drug design and development. Nat. Rev. Drug Discov. 2018;17:559–587. doi: 10.1038/nrd.2018.46. PubMed DOI

Rautio J., Kärkkäinen J., Sloan K.B. Prodrugs—Recent approvals and a glimpse of the pipeline. Eur. J. Pharm. Sci. 2017;109:146–161. doi: 10.1016/j.ejps.2017.08.002. PubMed DOI

Colas C., Ung P.M.-U., Schlessinger A. SLC transporters: Structure, function, and drug discovery. MedChemComm. 2016;7:1069–1081. doi: 10.1039/C6MD00005C. PubMed DOI PMC

Majumder P., Mallela A.K., Penmatsa A. Transporters Through the Looking Glass: An Insight into the Mechanisms of Ion-Coupled Transport and Methods That Help Reveal Them. J. Indian Inst. Sci. 2018;98:283–300. doi: 10.1007/s41745-018-0081-5. PubMed DOI PMC

Januliene D., Moeller A. Cryo-EM of ABC transporters: An ice-cold solution to everything? FEBS Lett. 2020;594:3776–3789. doi: 10.1002/1873-3468.13989. PubMed DOI

Schlessinger A., Welch M.A., Van Vlijmen H., Korzekwa K., Swaan P.W., Matsson P. Molecular Modeling of Drug-Transporter Interactions-An International Transporter Consortium Perspective. Clin. Pharmacol. Ther. 2018;104:818–835. doi: 10.1002/cpt.1174. PubMed DOI PMC

Magi S., Piccirillo S., Amoroso S., Lariccia V. Excitatory Amino Acid Transporters (EAATs): Glutamate Transport and Beyond. Int. J. Mol. Sci. 2019;20:5674. doi: 10.3390/ijms20225674. PubMed DOI PMC

O’Kane R.L., Martínez-López I., DeJoseph M.R., Viña J.R., Hawkins R.A. Na(+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal. J. Biol. Chem. 1999;274:31891–31895. doi: 10.1074/jbc.274.45.31891. PubMed DOI

Rothstein J.D., Martin L., Levey A.I., Dykes-Hoberg M., Jin L., Wu D., Nash N., Kuncl R.W. Localization of neuronal and glial glutamate transporters. Neuron. 1994;13:713–725. doi: 10.1016/0896-6273(94)90038-8. PubMed DOI

Danbolt N.C. Glutamate uptake. Prog. Neurobiol. 2001;65:1–105. doi: 10.1016/S0301-0082(00)00067-8. PubMed DOI

Malik A.R., Willnow T.E. Excitatory Amino Acid Transporters in Physiology and Disorders of the Central Nervous System. Int. J. Mol. Sci. 2019;20:5671. doi: 10.3390/ijms20225671. PubMed DOI PMC

Lee S.-G., Su Z.-Z., Emdad L., Gupta P., Sarkar D., Borjabad A., Volsky D.J., Fisher P.B. Mechanism of Ceftriaxone Induction of Excitatory Amino Acid Transporter-2 Expression and Glutamate Uptake in Primary Human Astrocytes. J. Biol. Chem. 2008;283:13116–13123. doi: 10.1074/jbc.M707697200. PubMed DOI PMC

Rothstein J.D., Patel S., Regan M.R., Haenggeli C., Huang Y.H., Bergles D.E., Jin L., Hoberg M.D., Vidensky S., Chung D.S., et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005;433:73–77. doi: 10.1038/nature03180. PubMed DOI

Underhill S.M., Wheeler D.S., Li M., Watts S.D., Ingram S.L., Amara S. Amphetamine Modulates Excitatory Neurotransmission through Endocytosis of the Glutamate Transporter EAAT3 in Dopamine Neurons. Neuron. 2014;83:404–416. doi: 10.1016/j.neuron.2014.05.043. PubMed DOI PMC

Jensen A.A., Erichsen M.N., Nielsen C.W., Stensbøl T.B., Kehler J., Bunch L. Discovery of the First Selective Inhibitor of Excitatory Amino Acid Transporter Subtype 1. J. Med. Chem. 2009;52:912–915. doi: 10.1021/jm8013458. PubMed DOI

Dunlop J., McIlvain H.B., Carrick T.A., Jow B., Lu Q., Kowal D., Lin S., Greenfield A., Grosanu C., Fan K., et al. Characterization of Novel Aryl-Ether, Biaryl, and Fluorene Aspartic Acid and Diaminopropionic Acid Analogs as Potent Inhibitors of the High-Affinity Glutamate Transporter EAAT2. Mol. Pharmacol. 2005;68:974–982. doi: 10.1124/mol.105.012005. PubMed DOI

Wu P., Bjørn-Yoshimoto W.E., Staudt M., Jensen A.A., Bunch L. Identification and Structure-Activity Relationship Study of Imidazo[1,2-a]pyridine-3-amines as First Selective Inhibitors of Excitatory Amino Acid Transporter Subtype 3 (EAAT3) ACS Chem. Neurosci. 2019;10:4414–4429. doi: 10.1021/acschemneuro.9b00447. PubMed DOI

Dholkawala F., Voshavar C., Dutta A.K. Synthesis and characterization of brain penetrant prodrug of neuroprotective D-264: Potential therapeutic application in the treatment of Parkinson’s disease. Eur. J. Pharm. Biopharm. 2016;103:62–70. doi: 10.1016/j.ejpb.2016.03.017. PubMed DOI

Weiss M.D., Rossignol C., Sumners C., Anderson K.J. A pH-dependent increase in neuronal glutamate efflux in vitro: Possible involvement of ASCT1. Brain Res. 2005;1056:105–112. doi: 10.1016/j.brainres.2005.07.045. PubMed DOI

Bröer A., Brookes N., Ganapathy V., Dimmer K.S., Wagner C.A., Lang F., Bröer S. The astroglial ASCT2 amino acid transporter as a mediator of glutamine efflux. J. Neurochem. 1999;73:2184–2194. doi: 10.1046/j.1471-4159.1999.02184.x. PubMed DOI

Gliddon C.M., Shao Z., LeMaistre J.L., Anderson C.M. Cellular distribution of the neutral amino acid transporter subtype ASCT2 in mouse brain. J. Neurochem. 2009;108:372–383. doi: 10.1111/j.1471-4159.2008.05767.x. PubMed DOI

Weiss M.D., Derazi S., Kilberg M.S., Anderson K.J. Ontogeny and localization of the neutral amino acid transporter ASCT1 in rat brain. Dev. Brain Res. 2001;130:183–190. doi: 10.1016/S0165-3806(01)00250-4. PubMed DOI

Sakai K., Shimizu H., Koike T., Furuya S., Watanabe M. Neutral Amino Acid Transporter ASCT1 Is Preferentially Expressed in l-Ser-Synthetic/Storing Glial Cells in the Mouse Brain with Transient Expression in Developing Capillaries. J. Neurosci. 2003;23:550–560. doi: 10.1523/JNEUROSCI.23-02-00550.2003. PubMed DOI PMC

Kaplan E., Zubedat S., Radzishevsky I., Valenta A.C., Rechnitz O., Sason H., Sajrawi C., Bodner O., Konno K., Esaki K., et al. ASCT1 (Slc1a4) transporter is a physiologic regulator of brain d -serine and neurodevelopment. Proc. Natl. Acad. Sci. USA. 2018;115:9628–9633. doi: 10.1073/pnas.1722677115. PubMed DOI PMC

Fuchs B.C., Bode B.P. Amino acid transporters ASCT2 and LAT1 in cancer: Partners in crime? Semin. Cancer Biol. 2005;15:254–266. doi: 10.1016/j.semcancer.2005.04.005. PubMed DOI

Scalise M., Pochini L., Console L., Losso M.A., Indiveri C. The Human SLC1A5 (ASCT2) Amino Acid Transporter: From Function to Structure and Role in Cell Biology. Front. Cell Dev. Biol. 2018;6:96. doi: 10.3389/fcell.2018.00096. PubMed DOI PMC

Vig B.S., Huttunen K.M., Laine K., Rautio J. Amino acids as promoieties in prodrug design and development. Adv. Drug Deliv. Rev. 2013;65:1370–1385. doi: 10.1016/j.addr.2012.10.001. PubMed DOI

Scalise M., Console L., Cosco J., Pochini L., Galluccio M., Indiveri C. ASCT1 and ASCT2: Brother and Sister? SLAS Discov. 2021;26:1148–1163. doi: 10.1177/24725552211030288. PubMed DOI

Scopelliti A.J., Font J., Vandenberg R.J., Boudker O., Ryan R.M. Structural characterisation reveals insights into substrate recognition by the glutamine transporter ASCT2/SLC1A5. Nat. Commun. 2018;9:38. doi: 10.1038/s41467-017-02444-w. PubMed DOI PMC

Scopelliti A.J., Ryan R., Vandenberg R.J. Molecular Determinants for Functional Differences between Alanine-Serine-Cysteine Transporter 1 and Other Glutamate Transporter Family Members. J. Biol. Chem. 2013;288:8250–8257. doi: 10.1074/jbc.M112.441022. PubMed DOI PMC

Li Y.-X., Yang J.-Y., Alcantara M., Abelian G., Kulkarni A., Staubli U., Foster A.C. Inhibitors of the Neutral Amino Acid Transporters ASCT1 and ASCT2 Are Effective in In Vivo Models of Schizophrenia and Visual Dysfunction. J. Pharmacol. Exp. Ther. 2018;367:292–301. doi: 10.1124/jpet.118.251116. PubMed DOI

Grewer C., Grabsch E. New inhibitors for the neutral amino acid transporter ASCT2 reveal its Na+-dependent anion leak. J. Physiol. 2004;557:747–759. doi: 10.1113/jphysiol.2004.062521. PubMed DOI PMC

Albers T., Marsiglia W., Thomas T., Gameiro A., Grewer C. Defining Substrate and Blocker Activity of Alanine-Serine-Cysteine Transporter 2 (ASCT2) Ligands with Novel Serine Analogs. Mol. Pharmacol. 2011;81:356–365. doi: 10.1124/mol.111.075648. PubMed DOI PMC

Esslinger C.S., Cybulski K.A., Rhoderick J.F. Ngamma-aryl glutamine analogues as probes of the ASCT2 neutral amino acid transporter binding site. Bioorg. Med. Chem. 2005;13:1111–1118. doi: 10.1016/j.bmc.2004.11.028. PubMed DOI

Singh K., Tanui R., Gameiro A., Eisenberg G., Colas C., Schlessinger A., Grewer C. Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2. Bioorganic Med. Chem. Lett. 2016;27:398–402. doi: 10.1016/j.bmcl.2016.12.063. PubMed DOI PMC

Patching S.G. Glucose Transporters at the Blood-Brain Barrier: Function, Regulation and Gateways for Drug Delivery. Mol. Neurobiol. 2016;54:1046–1077. doi: 10.1007/s12035-015-9672-6. PubMed DOI

Buck A., Schirrmeister H., Mattfeldt T., Reske S.N. Biological characterisation of breast cancer by means of PET. Eur. J. Pediatr. 2004;31:S80–S87. doi: 10.1007/s00259-004-1529-6. PubMed DOI

Pliszka M., Szablewski L. Glucose Transporters as a Target for Anticancer Therapy. Cancers. 2021;13:4184. doi: 10.3390/cancers13164184. PubMed DOI PMC

Younes M., Lechago L.V., Somoano J.R., Mosharaf M., Lechago J. Wide expression of the human erythrocyte glucose transporter Glut1 in human cancers. Cancer Res. 1996;56:1164–1167. PubMed

Macheda M.L., Rogers S., Best J. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J. Cell. Physiol. 2004;202:654–662. doi: 10.1002/jcp.20166. PubMed DOI

Barron C.C., Bilan P.J., Tsakiridis T., Tsiani E. Facilitative glucose transporters: Implications for cancer detection, prognosis and treatment. Metabolism. 2015;65:124–139. doi: 10.1016/j.metabol.2015.10.007. PubMed DOI

Bonina F.P., Arenare L., Ippolito R., Boatto G., Battaglia G., Bruno V., de Caprariis P. Synthesis, pharmacokinetics and anticonvulsant activity of 7-chlorokynurenic acid prodrugs. Int. J. Pharm. 2000;202:79–88. doi: 10.1016/S0378-5173(00)00421-X. PubMed DOI

Bonina F., Puglia C., Rimoli M.G., Melisi D., Boatto G., Nieddu M., Calignano A., Rana G.L., Caprariis P. Glycosyl derivatives of dopamine and L-dopa as anti-Parkinson prodrugs: Synthesis, pharmacological activity and in vitro stability studies. J. Drug Target. 2003;11:25–36. doi: 10.1080/10611860305553. PubMed DOI

Fernández C., Nieto O., Fontenla J.A., Rivas E., de Ceballos M.L., Fernández-Mayoralas A. Synthesis of glycosyl derivatives as dopamine prodrugs: Interaction with glucose carrier GLUT-1. Org. Biomol. Chem. 2003;1:767–771. doi: 10.1039/b212066f. PubMed DOI

Halmos T., Santarromana M., Antonakis K., Scherman D. Synthesis of glucose-chlorambucil derivatives and their recognition by the human GLUT1 glucose transporter. Eur. J. Pharmacol. 1996;318:477–484. doi: 10.1016/S0014-2999(96)00796-0. PubMed DOI

Bilsky E.J., Egleton R.D., Mitchell S.A., Palian M.M., Davis P., Huber J.D., Jones H., Yamamura H.I., Janders J., Davis T.P., et al. Enkephalin Glycopeptide Analogues Produce Analgesia with Reduced Dependence Liability. J. Med. Chem. 2000;43:2586–2590. doi: 10.1021/jm000077y. PubMed DOI

Gynther M., Ropponen J., Laine K., Leppänen J., Haapakoski P., Peura L., Järvinen T., Rautio J. Glucose Promoiety Enables Glucose Transporter Mediated Brain Uptake of Ketoprofen and Indomethacin Prodrugs in Rats. J. Med. Chem. 2009;52:3348–3353. doi: 10.1021/jm8015409. PubMed DOI

Leenders R.G.G., Damen E.W.P., Bijsterveld E.J.A., Scheeren H.W., Houba P.H.J., Meulen-Muileman I.H., Boven E., Haisma H.J. Novel anthracycline-spacer-beta-glucuronide,-beta-glucoside, and -beta-galactoside prodrugs for application in selective chemotherapy. Bioorg. Med. Chem. 1999;7:1597–1610. doi: 10.1016/S0968-0896(99)00095-4. PubMed DOI

Tranoy-Opalinski I., Legigan T., Barat R., Clarhaut J., Thomas M., Renoux B., Papot S. β-Glucuronidase-responsive prodrugs for selective cancer chemotherapy: An update. Eur. J. Med. Chem. 2014;74:302–313. doi: 10.1016/j.ejmech.2013.12.045. PubMed DOI

Matović J., Järvinen J., Sokka I.K., Imlimthan S., Raitanen J.-E., Montaser A., Maaheimo H., Huttunen K.M., Peräniemi S., Airaksinen A.J., et al. Exploring the Biochemical Foundations of a Successful GLUT1-Targeting Strategy to BNCT: Chemical Synthesis and In Vitro Evaluation of the Entire Positional Isomer Library of ortho-Carboranylmethyl-Bearing Glucoconjugates. Mol. Pharm. 2020;18:285–304. doi: 10.1021/acs.molpharmaceut.0c00917. PubMed DOI

Zhang K., Xu P., Sowers J.L., Machuca D.F., Mirfattah B., Herring J., Tang H., Chen Y., Tian B., Brasier A.R., et al. Proteome Analysis of Hypoxic Glioblastoma Cells Reveals Sequential Metabolic Adaptation of One-Carbon Metabolic Pathways. Mol. Cell. Proteom. 2017;16:1906–1921. doi: 10.1074/mcp.RA117.000154. PubMed DOI PMC

Ohnishi K., Misawa M., Sikano N., Nakai K., Suzuki M. Enhancement of Cancer Cell-Killing Effects of Boron Neutron Capture Therapy by Manipulating the Expression of L-Type Amino Acid Transporter 1. Radiat. Res. 2021;196:17–22. doi: 10.1667/RADE-20-00214.1. PubMed DOI

Drew D., North R.A., Nagarathinam K., Tanabe M. Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS) Chem. Rev. 2021;121:5289–5335. doi: 10.1021/acs.chemrev.0c00983. PubMed DOI PMC

Galochkina T., Chong M.N.F., Challali L., Abbar S., Etchebest C. New insights into GluT1 mechanics during glucose transfer. Sci. Rep. 2019;9:998. doi: 10.1038/s41598-018-37367-z. PubMed DOI PMC

Gonzalez-Resines S., Quinn P.J., Naftalin R.J., Domene C. Multiple Interactions of Glucose with the Extra-Membranous Loops of GLUT1 Aid Transport. J. Chem. Inf. Model. 2021;61:3559–3570. doi: 10.1021/acs.jcim.1c00310. PubMed DOI

Park M.-S. Molecular Dynamics Simulations of the Human Glucose Transporter GLUT1. PLoS ONE. 2015;10:e0125361. doi: 10.1371/journal.pone.0125361. PubMed DOI PMC

Tachikawa M., Hirose S., Akanuma S.-I., Matsuyama R., Hosoya K.-I. Developmental changes of l -arginine transport at the blood-brain barrier in rats. Microvasc. Res. 2018;117:16–21. doi: 10.1016/j.mvr.2017.12.003. PubMed DOI

Hosokawa H., Ninomiya H., Sawamura T., Sugimoto Y., Ichikawa A., Fujiwara K., Masaki T. Neuron-specific expression of cationic amino acid transporter 3 in the adult rat brain. Brain Res. 1999;838:158–165. doi: 10.1016/S0006-8993(99)01686-8. PubMed DOI

Braissant O., Gotoh T., Loup M., Mori M., Bachmann C. Differential expression of the cationic amino acid transporter 2(B) in the adult rat brain. Mol. Brain Res. 2001;91:189–195. doi: 10.1016/S0169-328X(01)00113-9. PubMed DOI

Stevens B.R., Kakuda D.K., Yu K., Waters M., Vo C.B., Raizada M.K. Induced Nitric Oxide Synthesis Is Dependent on Induced Alternatively Spliced CAT-2 Encoding L-Arginine Transport in Brain Astrocytes. J. Biol. Chem. 1996;271:24017–24022. doi: 10.1074/jbc.271.39.24017. PubMed DOI

Zaragozá R. Transport of Amino Acids Across the Blood-Brain Barrier. Front. Physiol. 2020;11:973. doi: 10.3389/fphys.2020.00973. PubMed DOI PMC

Huang Y., Kang B.N., Tian J., Liu Y., Luo H.R., Hester L., Snyder S.H. The Cationic Amino Acid Transporters CAT1 and CAT3 Mediate NMDA Receptor Activation-Dependent Changes in Elaboration of Neuronal Processes via the Mammalian Target of Rapamycin mTOR Pathway. J. Neurosci. 2007;27:449–458. doi: 10.1523/JNEUROSCI.4489-06.2007. PubMed DOI PMC

Dai R., Peng F., Xiao X., Gong X., Jiang Y., Zhang M., Tian Y., Xu Y., Ma J., Li M., et al. Hepatitis B virus X protein-induced upregulation of CAT-1 stimulates proliferation and inhibits apoptosis in hepatocellular carcinoma cells. Oncotarget. 2017;8:60962–60974. doi: 10.18632/oncotarget.17631. PubMed DOI PMC

Abdelmagid S.A., Rickard J.A., McDonald W.J., Thomas L.N., Too C.K. CAT-1-mediated arginine uptake and regulation of nitric oxide synthases for the survival of human breast cancer cell lines. J. Cell. Biochem. 2011;112:1084–1092. doi: 10.1002/jcb.23022. PubMed DOI

Lu Y., Wang W., Wang J., Yang C., Mao H., Fu X., Wu Y., Cai J., Han J., Xu Z., et al. Overexpression of Arginine Transporter CAT-1 Is Associated with Accumulation of L-Arginine and Cell Growth in Human Colorectal Cancer Tissue. PLoS ONE. 2013;8:e73866. doi: 10.1371/journal.pone.0073866. PubMed DOI PMC

Werner A., Pieh D., Echchannaoui H., Rupp J., Rajalingam K., Theobald M., Closs E.I., Munder M. Cationic Amino Acid Transporter-1-Mediated Arginine Uptake Is Essential for Chronic Lymphocytic Leukemia Cell Proliferation and Viability. Front. Oncol. 2019;9:1268. doi: 10.3389/fonc.2019.01268. PubMed DOI PMC

Jungnickel K.E.J., Parker J., Newstead S. Structural basis for amino acid transport by the CAT family of SLC7 transporters. Nat. Commun. 2018;9:550. doi: 10.1038/s41467-018-03066-6. PubMed DOI PMC

Fort J., Nicolàs-Aragó A., Palacín M. The Ectodomains of rBAT and 4F2hc Are Fake or Orphan α-Glucosidases. Molecules. 2021;26:6231. doi: 10.3390/molecules26206231. PubMed DOI PMC

Estrach S., Lee S.-A., Boulter E., Pisano S., Errante A., Tissot F.S., Cailleteau L., Pons C., Ginsberg M.H., Féral C.C. CD98hc (SLC3A2) Loss Protects Against Ras-Driven Tumorigenesis by Modulating Integrin-Mediated Mechanotransduction. Cancer Res. 2014;74:6878–6889. doi: 10.1158/0008-5472.CAN-14-0579. PubMed DOI PMC

Feral C.C., Nishiya N., Fenczik C.A., Stuhlmann H., Slepak M., Ginsberg M.H. CD98hc (SLC3A2) mediates integrin signaling. Proc. Natl. Acad. Sci. USA. 2004;102:355–360. doi: 10.1073/pnas.0404852102. PubMed DOI PMC

Kanai Y., Segawa H., Miyamoto K.-I., Uchino H., Takeda E., Endou H. Expression Cloning and Characterization of a Transporter for Large Neutral Amino Acids Activated by the Heavy Chain of 4F2 Antigen (CD98) J. Biol. Chem. 1998;273:23629–23632. doi: 10.1074/jbc.273.37.23629. PubMed DOI

Prasad P.D., Wang H., Huang W., Kekuda R., Rajan D.P., Leibach F.H., Ganapathy V. Human LAT1, a Subunit of System L Amino Acid Transporter: Molecular Cloning and Transport Function. Biochem. Biophys. Res. Commun. 1999;255:283–288. doi: 10.1006/bbrc.1999.0206. PubMed DOI

Boado R.J., Li J.Y., Nagaya M., Zhang C., Pardridge W.M. Selective expression of the large neutral amino acid transporter at the blood–brain barrier. Proc. Natl. Acad. Sci. USA. 1999;96:12079–12084. doi: 10.1073/pnas.96.21.12079. PubMed DOI PMC

Scalise M., Galluccio M., Console L., Pochini L., Indiveri C. The Human SLC7A5 (LAT1): The Intriguing Histidine/Large Neutral Amino Acid Transporter and Its Relevance to Human Health. Front. Chem. 2018;6:243. doi: 10.3389/fchem.2018.00243. PubMed DOI PMC

Huttunen J., Peltokangas S., Gynther M., Natunen T., Hiltunen M., Auriola S., Ruponen M., Vellonen K.-S., Huttunen K.M. L-Type Amino Acid Transporter 1 (LAT1/Lat1)-Utilizing Prodrugs Can Improve the Delivery of Drugs into Neurons, Astrocytes and Microglia. Sci. Rep. 2019;9:12860. doi: 10.1038/s41598-019-49009-z. PubMed DOI PMC

Duelli R., Enerson B.E., Gerhart D.Z., Drewes L.R. Expression of Large Amino Acid Transporter LAT1 in Rat Brain Endothelium. J. Cereb. Blood Flow Metab. 2000;20:1557–1562. doi: 10.1097/00004647-200011000-00005. PubMed DOI

Yanagida O., Kanai Y., Chairoungdua A., Kim D.K., Segawa H., Nii T., Cha S.H., Matsuo H., Fukushima J.-I., Fukasawa Y., et al. Human L-type amino acid transporter 1 (LAT1): Characterization of function and expression in tumor cell lines. Biochim. Biophys. Acta Biomembr. 2001;1514:291–302. doi: 10.1016/S0005-2736(01)00384-4. PubMed DOI

Wang Q., Holst J. L-type amino acid transport and cancer: Targeting the mTORC1 pathway to inhibit neoplasia. Am. J. Cancer Res. 2015;5:1281–1294. PubMed PMC

Häfliger P., Charles R.-P. The L-Type Amino Acid Transporter LAT1—An Emerging Target in Cancer. Int. J. Mol. Sci. 2019;20:2428. doi: 10.3390/ijms20102428. PubMed DOI PMC

Furuya M., Horiguchi J., Nakajima H., Kanai Y., Oyama T. Correlation of L-type amino acid transporter 1 and CD98 expression with triple negative breast cancer prognosis. Cancer Sci. 2011;103:382–389. doi: 10.1111/j.1349-7006.2011.02151.x. PubMed DOI

Sakata T., Ferdous G., Tsuruta T., Satoh T., Baba S., Muto T., Ueno A., Kanai Y., Endou H., Okayasu I. L-type amino-acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer. Pathol. Int. 2009;59:7–18. doi: 10.1111/j.1440-1827.2008.02319.x. PubMed DOI

Hayashi K., Anzai N. Novel therapeutic approaches targeting L-type amino acid transporters for cancer treatment. World J. Gastrointest. Oncol. 2017;9:21–29. doi: 10.4251/wjgo.v9.i1.21. PubMed DOI PMC

Tărlungeanu D.C., Deliu E., Dotter C.P., Kara M., Janiesch P.C., Scalise M., Galluccio M., Tesulov M., Morelli E., Sonmez F.M., et al. Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder. Cell. 2016;167:1481–1494. doi: 10.1016/j.cell.2016.11.013. PubMed DOI PMC

Kärkkäinen J., Gynther M., Kokkola T., Petsalo A., Auriola S., Lahtela-Kakkonen M., Laine K., Rautio J., Huttunen K.M. Structural properties for selective and efficient l-type amino acid transporter 1 (LAT1) mediated cellular uptake. Int. J. Pharm. 2018;544:91–99. doi: 10.1016/j.ijpharm.2018.04.025. PubMed DOI

Kärkkäinen J., Laitinen T., Markowicz-Piasecka M., Montaser A., Lehtonen M., Rautio J., Gynther M., Poso A., Huttunen K.M. Molecular characteristics supporting l-Type amino acid transporter 1 (LAT1)-mediated translocation. Bioorganic Chem. 2021;112:104921. doi: 10.1016/j.bioorg.2021.104921. PubMed DOI

Lee Y., Wiriyasermkul P., Jin C., Quan L., Ohgaki R., Okuda S., Kusakizako T., Nishizawa T., Oda K., Ishitani R., et al. Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc. Nat. Struct. Mol. Biol. 2019;26:510–517. doi: 10.1038/s41594-019-0237-7. PubMed DOI

Yan R., Zhao X., Lei J., Zhou Q. Structure of the human LAT1–4F2hc heteromeric amino acid transporter complex. Nature. 2019;568:127–130. doi: 10.1038/s41586-019-1011-z. PubMed DOI

Chien H.-C., Colas C., Finke K., Springer S., Stoner L., Zur A.A., Venteicher B., Campbell J., Hall C., Flint A., et al. Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1) J. Med. Chem. 2018;61:7358–7373. doi: 10.1021/acs.jmedchem.8b01007. PubMed DOI PMC

Tampio J., Löffler S., Guillon M., Hugele A., Huttunen J., Huttunen K.M. Improved l-Type amino acid transporter 1 (LAT1)-mediated delivery of anti-inflammatory drugs into astrocytes and microglia with reduced prostaglandin production. Int. J. Pharm. 2021;601:120565. doi: 10.1016/j.ijpharm.2021.120565. PubMed DOI

Forrest L., Rudnick G. The Rocking Bundle: A Mechanism for Ion-Coupled Solute Flux by Symmetrical Transporters. Physiology. 2009;24:377–386. doi: 10.1152/physiol.00030.2009. PubMed DOI PMC

Gynther M., Peura L., Vernerová M., Leppänen J., Kärkkäinen J., Lehtonen M., Rautio J., Huttunen K.M. Amino Acid Promoieties Alter Valproic Acid Pharmacokinetics and Enable Extended Brain Exposure. Neurochem. Res. 2016;41:2797–2809. doi: 10.1007/s11064-016-1996-8. PubMed DOI

Gynther M., Pickering D.S., Spicer J.A., Denny W.A., Huttunen K.M. Systemic and Brain Pharmacokinetics of Perforin Inhibitor Prodrugs. Mol. Pharm. 2016;13:2484–2491. doi: 10.1021/acs.molpharmaceut.6b00217. PubMed DOI

Montaser A.B., Järvinen J., Löffler S., Huttunen J., Auriola S., Lehtonen M., Jalkanen A., Huttunen K.M. L-Type Amino Acid Transporter 1 Enables the Efficient Brain Delivery of Small-Sized Prodrug across the Blood–Brain Barrier and into Human and Mouse Brain Parenchymal Cells. ACS Chem. Neurosci. 2020;11:4301–4315. doi: 10.1021/acschemneuro.0c00564. PubMed DOI

Peura L., Malmioja K., Huttunen K., Leppänen J., Hämäläinen M., Forsberg M.M., Rautio J., Laine K. Design, Synthesis and Brain Uptake of LAT1-Targeted Amino Acid Prodrugs of Dopamine. Pharm. Res. 2013;30:2523–2537. doi: 10.1007/s11095-012-0966-3. PubMed DOI

Puris E., Gynther M., Huttunen J., Petsalo A., Huttunen K.M. L-type amino acid transporter 1 utilizing prodrugs: How to achieve effective brain delivery and low systemic exposure of drugs. J. Control. Release. 2017;261:93–104. doi: 10.1016/j.jconrel.2017.06.023. PubMed DOI

Puris E., Gynther M., Huttunen J., Auriola S., Huttunen K.M. L-type amino acid transporter 1 utilizing prodrugs of ferulic acid revealed structural features supporting the design of prodrugs for brain delivery. Eur. J. Pharm. Sci. 2019;129:99–109. doi: 10.1016/j.ejps.2019.01.002. PubMed DOI

Hokari M., Wu H.-Q., Schwarcz R., Smith Q.R. Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid. NeuroReport. 1996;8:15–18. doi: 10.1097/00001756-199612200-00004. PubMed DOI

Okano N., Naruge D., Kawai K., Kobayashi T., Nagashima F., Endou H., Furuse J. First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors. Investig. New Drugs. 2020;38:1495–1506. doi: 10.1007/s10637-020-00924-3. PubMed DOI

Segawa H., Fukasawa Y., Miyamoto K.-I., Takeda E., Endou H., Kanai Y. Identification and Functional Characterization of a Na+-independent Neutral Amino Acid Transporter with Broad Substrate Selectivity. J. Biol. Chem. 1999;274:19745–19751. doi: 10.1074/jbc.274.28.19745. PubMed DOI

Pineda M., Fernández E., Torrents D., Estevez R., López C., Camps M., Lloberas J., Zorzano A., Palacín M. Identification of a Membrane Protein, LAT-2, That Co-expresses with 4F2 Heavy Chain, an L-type Amino Acid Transport Activity with Broad Specificity for Small and Large Zwitterionic Amino Acids. J. Biol. Chem. 1999;274:19738–19744. doi: 10.1074/jbc.274.28.19738. PubMed DOI

Bröer A., Wagner C.A., Lang F., Bröer S. The heterodimeric amino acid transporter 4F2hc/y+LAT2 mediates arginine efflux in exchange with glutamine. Biochem. J. 2000;349:787–795. doi: 10.1042/bj3490787. PubMed DOI PMC

Meier C., Ristic Z., Klauser S., Verrey F. Activation of system L heterodimeric amino acid exchangers by intracellular substrates. EMBO J. 2002;21:580–589. doi: 10.1093/emboj/21.4.580. PubMed DOI PMC

Braun D., Kinne A., Bräuer A.U., Sapin R., Klein M.O., Köhrle J., Wirth E.K., Schweizer U. Developmental and cell type-specific expression of thyroid hormone transporters in the mouse brain and in primary brain cells. Glia. 2010;59:463–471. doi: 10.1002/glia.21116. PubMed DOI

Milewski K., Bogacińska-Karaś M., Fręśko I., Hilgier W., Jaźwiec R., Albrecht J., Zielińska M. Ammonia Reduces Intracellular Asymmetric Dimethylarginine in Cultured Astrocytes Stimulating Its y+LAT2 Carrier-Mediated Loss. Int. J. Mol. Sci. 2017;18:2308. doi: 10.3390/ijms18112308. PubMed DOI PMC

Zielińska M., Milewski K., Skowrońska M., Gajos A., Zieminska E., Beręsewicz A., Albrecht J.K. Induction of inducible nitric oxide synthase expression in ammonia-exposed cultured astrocytes is coupled to increased arginine transport by upregulated y+ LAT2 transporter. J. Neurochem. 2015;135:1272–1281. doi: 10.1111/jnc.13387. PubMed DOI

Kinne A., Wittner M., Wirth E.K., Hinz K.M., Schülein R., Köhrle J., Krause G. Involvement of the L-Type Amino Acid Transporter Lat2 in the Transport of 3,3′-Diiodothyronine across the Plasma Membrane. Eur. Thyroid J. 2015;4:42–50. doi: 10.1159/000381542. PubMed DOI PMC

Zevenbergen C., Meima M.E., Lima de Souza E.C., Peeters R.P., Kinne A., Krause G., Visser W.E., Visser T.J. Transport of Iodothyronines by Human L-Type Amino Acid Transporters. Endocrinology. 2015;156:4345–4355. doi: 10.1210/en.2015-1140. PubMed DOI

Pinto V., Pinho M.J., Soares-Da-Silva P. Renal amino acid transport systems and essential hypertension. FASEB J. 2013;27:2927–2938. doi: 10.1096/fj.12-224998. PubMed DOI

Barollo S., Bertazza L., Fernando S.W., Censi S., Cavedon E., Galuppini F., Pennelli G., Fassina A., Citton M., Rubin B., et al. Overexpression of L-Type Amino Acid Transporter 1 (LAT1) and 2 (LAT2): Novel Markers of Neuroendocrine Tumors. PLoS ONE. 2016;11:e0156044. doi: 10.1371/journal.pone.0156044. PubMed DOI PMC

Feng M., Xiong G., Cao Z., Yang G., Zheng S., Qiu J., You L., Zheng L., Zhang T., Zhao Y. LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer. J. Exp. Clin. Cancer Res. 2018;37:274. doi: 10.1186/s13046-018-0947-4. PubMed DOI PMC

Yan R., Zhou J., Li Y., Lei J., Zhou Q. Structural insight into the substrate recognition and transport mechanism of the human LAT2–4F2hc complex. Cell Discov. 2020;6:82. doi: 10.1038/s41421-020-00207-4. PubMed DOI PMC

Nakauchi J., Matsuo H., Kim D.K., Goto A., Chairoungdua A., Cha S.H., Inatomi J., Shiokawa Y., Yamaguchi K., Saito I., et al. Cloning and characterization of a human brain Na+-independent transporter for small neutral amino acids that transports d-serine with high affinity. Neurosci. Lett. 2000;287:231–235. doi: 10.1016/S0304-3940(00)01169-1. PubMed DOI

Fukasawa Y., Segawa H., Kim J.Y., Chairoungdua A., Kim D.K., Matsuo H., Cha S.H., Endou H., Kanai Y. Identification and Characterization of a Na+-independent Neutral Amino Acid Transporter That Associates with the 4F2 Heavy Chain and Exhibits Substrate Selectivity for Small Neutral d- and l-Amino Acids. J. Biol. Chem. 2000;275:9690–9698. doi: 10.1074/jbc.275.13.9690. PubMed DOI

Bassi M., Gasol E., Manzoni M., Pineda M., Riboni M., Martín R., Zorzano A., Borsani G., Palacín M. Identification and characterisation of human xCT that co-expresses, with 4F2 heavy chain, the amino acid transport activity system x c–. Pflüg. Arch. 2001;442:286–296. doi: 10.1007/s004240100537. PubMed DOI

Sato H., Tamba M., Ishii T., Bannai S. Cloning and Expression of a Plasma Membrane Cystine/Glutamate Exchange Transporter Composed of Two Distinct Proteins. J. Biol. Chem. 1999;274:11455–11458. doi: 10.1074/jbc.274.17.11455. PubMed DOI

Rutter A.R., Fradley R.L., Garrett E.M., Chapman K.L., Lawrence J.M., Rosahl T.W., Patel S. Evidence from gene knockout studies implicates Asc-1 as the primary transporter mediating d-serine reuptake in the mouse CNS. Eur. J. Neurosci. 2007;25:1757–1766. doi: 10.1111/j.1460-9568.2007.05446.x. PubMed DOI

Helboe L., Egebjerg J., Møller M., Thomsen C. Distribution and pharmacology of alanine-serine-cysteine transporter 1 (asc-1) in rodent brain. Eur. J. Neurosci. 2003;18:2227–2238. doi: 10.1046/j.1460-9568.2003.02966.x. PubMed DOI

Xie X., Dumas T., Tang L., Brennan T., Reeder T., Thomas W., Klein R.D., Flores J., O’Hara B.F., Heller H.C., et al. Lack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice. Brain Res. 2005;1052:212–221. doi: 10.1016/j.brainres.2005.06.039. PubMed DOI

Seib T.M., Patel S.A., Bridges R.J. Regulation of the System x−C cystine/glutamate exchanger by intracellular glutathione levels in rat astrocyte primary cultures. Glia. 2011;59:1387–1401. doi: 10.1002/glia.21176. PubMed DOI

Lewerenz J., Maher P., Methner A. Regulation of xCT expression and system x (c) (-) function in neuronal cells. Amino Acids. 2012;42:171–179. doi: 10.1007/s00726-011-0862-x. PubMed DOI

Lewerenz J., Hewett S.J., Huang Y., Lambros M., Gout P.W., Kalivas P.W., Massie A., Smolders I., Methner A., Pergande M., et al. The cystine/glutamate antiporter system x(c)(-) in health and disease: From molecular mechanisms to novel therapeutic opportunities. Antioxid. Redox Signal. 2013;18:522–555. doi: 10.1089/ars.2011.4391. PubMed DOI PMC

Sato M., Onuma K., Domon M., Hasegawa S., Suzuki A., Kusumi R., Hino R., Kakihara N., Kanda Y., Osaki M., et al. Loss of the cystine/glutamate antiporter in melanoma abrogates tumor metastasis and markedly increases survival rates of mice. Int. J. Cancer. 2020;147:3224–3235. doi: 10.1002/ijc.33262. PubMed DOI

Conrad M., Sato H. The oxidative stress-inducible cystine/glutamate antiporter, system x (c) (-): Cystine supplier and beyond. Amino Acids. 2012;42:231–246. doi: 10.1007/s00726-011-0867-5. PubMed DOI

Kutchukian P.S., Warren L., Magliaro B.C., Amoss A., Cassaday J.A., O’Donnell G., Squadroni B., Zuck P., Pascarella D., Culberson J.C., et al. Iterative Focused Screening with Biological Fingerprints Identifies Selective Asc-1 Inhibitors Distinct from Traditional High Throughput Screening. ACS Chem. Biol. 2017;12:519–527. doi: 10.1021/acschembio.6b00913. PubMed DOI

Patel D., Kharkar P.S., Gandhi N.S., Kaur E., Dutt S., Nandave M. Novel analogs of sulfasalazine as system x(c) (-) antiporter inhibitors: Insights from the molecular modeling studies. Drug Dev. Res. 2019;80:758–777. doi: 10.1002/ddr.21557. PubMed DOI

Halestrap A.P. The monocarboxylate transporter family-Structure and functional characterization. IUBMB Life. 2011;64:1–9. doi: 10.1002/iub.573. PubMed DOI

Halestrap A.P. The SLC16 gene family—Structure, role and regulation in health and disease. Mol. Asp. Med. 2013;34:337–349. doi: 10.1016/j.mam.2012.05.003. PubMed DOI

Halestrap A.P., Meredith D. The SLC16 gene family?from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflug. Arch. 2003;447:619–628. doi: 10.1007/s00424-003-1067-2. PubMed DOI

Chiry O., Pellerin L., Monnet-Tschudi F., Fishbein W.N., Merezhinskaya N., Magistretti P.J., Clarke S. Expression of the monocarboxylate transporter MCT1 in the adult human brain cortex. Brain Res. 2006;1070:65–70. doi: 10.1016/j.brainres.2005.11.064. PubMed DOI

Halestrap A.P., Wilson M.C. The monocarboxylate transporter family-Role and regulation. IUBMB Life. 2011;64:109–119. doi: 10.1002/iub.572. PubMed DOI

Deguchi Y., Nozawa K., Yamada S., Yokoyama Y., Kimura R. Quantitative evaluation of brain distribution and blood-brain barrier efflux transport of probenecid in rats by microdialysis: Possible involvement of the monocarboxylic acid transport system. J. Pharmacol. Exp. Ther. 1997;280:551–560. PubMed

Deguchi Y., Yokoyama Y., Sakamoto T., Hayashi H., Naito T., Yamada S., Kimura R. Brain distribution of 6-mercaptopurine is regulated by the efflux transport system in the blood-brain barrier 1. Life Sci. 2000;66:649–662. doi: 10.1016/S0024-3205(99)00637-2. PubMed DOI

Felmlee M.A., Morse B.L., Morris M.E. γ-Hydroxybutyric Acid: Pharmacokinetics, Pharmacodynamics, and Toxicology. AAPS J. 2021;23:22. doi: 10.1208/s12248-020-00543-z. PubMed DOI PMC

Lee N.-Y., Kang Y.-S. In Vivo and In Vitro Evidence for Brain Uptake of 4-Phenylbutyrate by the Monocarboxylate Transporter 1 (MCT1) Pharm. Res. 2016;33:1711–1722. doi: 10.1007/s11095-016-1912-6. PubMed DOI

Kang Y., Terasaki T., Tsuji A. Acidic drug transport in vivo through the blood-brain barrier. A role of the transport carrier for monocarboxylic acids. J. Pharm. Dyn. 1990;13:158–163. doi: 10.1248/bpb1978.13.158. PubMed DOI

Terasaki T., Takakuwa S., Moritani S., Tsuji A. Transport of monocarboxylic acids at the blood-brain barrier: Studies with monolayers of primary cultured bovine brain capillary endothelial cells. J. Pharmacol. Exp. Ther. 1991;258:932–937. PubMed

Friesema E.C.H., Ganguly S., Abdalla A., Manning Fox J.E., Halestrap A.P., Visser T.J. Identification of Monocarboxylate Transporter 8 as a Specific Thyroid Hormone Transporter. J. Biol. Chem. 2003;278:40128–40135. doi: 10.1074/jbc.M300909200. PubMed DOI

Roberts L.M., Woodford K., Zhou M., Black D.S., Haggerty J.E., Tate E.H., Grindstaff K.K., Mengesha W., Raman C., Zerangue N. Expression of the Thyroid Hormone Transporters Monocarboxylate Transporter-8 (SLC16A2) and Organic Ion Transporter-14 (SLCO1C1) at the Blood-Brain Barrier. Endocrinology. 2008;149:6251–6261. doi: 10.1210/en.2008-0378. PubMed DOI

Heuer H., Maier M.K., Iden S., Mittag J., Friesema E.C.H., Visser T.J., Bauer K. The Monocarboxylate Transporter 8 Linked to Human Psychomotor Retardation Is Highly Expressed in Thyroid Hormone-Sensitive Neuron Populations. Endocrinology. 2005;146:1701–1706. doi: 10.1210/en.2004-1179. PubMed DOI

Groeneweg S., Geest F.S., Peeters R.P., Heuer H., Visser W.E. Thyroid Hormone Transporters. Endocr. Rev. 2020;41:146–201. doi: 10.1210/endrev/bnz008. PubMed DOI

Di Cosmo C., De Marco G., Agretti P., Ferrarini E., Dimida A., Falcetta P., Benvenga S., Vitti P., Tonacchera M. Screening for drugs potentially interfering with MCT8-mediated T3 transport in vitro identifies dexamethasone and some commonly used drugs as inhibitors of MCT8 activity. J. Endocrinol. Investig. 2021;45:803–814. doi: 10.1007/s40618-021-01711-4. PubMed DOI

Bergersen L.H. Lactate Transport and Signaling in the Brain: Potential Therapeutic Targets and Roles in Body—Brain Interaction. J. Cereb. Blood Flow Metab. 2014;35:176–185. doi: 10.1038/jcbfm.2014.206. PubMed DOI PMC

Bröer S., Rahman B., Pellegri G., Pellerin L., Martin J.-L., Verleysdonk S., Hamprecht B., Magistretti P.J. Comparison of Lactate Transport in Astroglial Cells and Monocarboxylate Transporter 1 (MCT 1) Expressing Xenopus laevis Oocytes. J. Biol. Chem. 1997;272:30096–30102. doi: 10.1074/jbc.272.48.30096. PubMed DOI

Lin R.-Y., Vera J.C., Chaganti R.S.K., Golde D.W. Human Monocarboxylate Transporter 2 (MCT2) Is a High Affinity Pyruvate Transporter. J. Biol. Chem. 1998;273:28959–28965. doi: 10.1074/jbc.273.44.28959. PubMed DOI

Philp N.J., Wang D., Yoon H., Hjelmeland L.M. Polarized Expression of Monocarboxylate Transporters in Human Retinal Pigment Epithelium and ARPE-19 Cells. Investig. Ophthalmol. Vis. Sci. 2003;44:1716–1721. doi: 10.1167/iovs.02-0287. PubMed DOI

Kobayashi M., Otsuka Y., Itagaki S., Hirano T., Iseki K. Inhibitory effects of statins on human monocarboxylate transporter 4. Int. J. Pharm. 2006;317:19–25. doi: 10.1016/j.ijpharm.2006.02.043. PubMed DOI

Dimmer K.S., Friedrich B., Lang F., Deitmer J.W., Bröer S. The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem. J. 2000;350:219–227. doi: 10.1042/bj3500219. PubMed DOI PMC

Gandhi G.K., Cruz N.F., Ball K.K., Dienel G.A. Astrocytes are poised for lactate trafficking and release from activated brain and for supply of glucose to neurons. J. Neurochem. 2009;111:522–536. doi: 10.1111/j.1471-4159.2009.06333.x. PubMed DOI PMC

Cheng C., Edin N.F.J., Lauritzen K.H., Aspmodal I., Christoffersen S., Jian L., Rasmussen L.J., Pettersen E.O., Xiaoqun G., Bergersen L.H. Alterations of monocarboxylate transporter densities during hypoxia in brain and breast tumour cells. Cell. Oncol. 2012;35:217–227. doi: 10.1007/s13402-012-0081-9. PubMed DOI PMC

Pinheiro C., Longatto-Filho A., Azevedo-Silva J., Casal M., Schmitt F.C., Baltazar F. Role of monocarboxylate transporters in human cancers: State of the art. J. Bioenerg. Biomembr. 2012;44:127–139. doi: 10.1007/s10863-012-9428-1. PubMed DOI

Curtis N.J., Mooney L., Hopcroft L., Michopoulos F., Whalley N., Zhong H., Murray C., Logie A., Revill M., Byth K.F., et al. Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt’s lymphoma anti-tumor activity. Oncotarget. 2017;8:69219–69236. doi: 10.18632/oncotarget.18215. PubMed DOI PMC

Felmlee M.A., Jones R.S., Rodriguez-Cruz V., Follman K.E., Morris M.E. Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease. Pharmacol. Rev. 2020;72:466–485. doi: 10.1124/pr.119.018762. PubMed DOI PMC

Guan X., Morris M.E. In Vitro and In Vivo Efficacy of AZD3965 and Alpha-Cyano-4-Hydroxycinnamic Acid in the Murine 4T1 Breast Tumor Model. AAPS J. 2020;22:84. doi: 10.1208/s12248-020-00466-9. PubMed DOI PMC

Medin T., Medin H., Hefte M.B., Storm-Mathisen J., Bergersen L.H. Upregulation of the lactate transporter monocarboxylate transporter 1 at the blood-brain barrier in a rat model of attention-deficit/hyperactivity disorder suggests hyperactivity could be a form of self-treatment. Behav. Brain Res. 2018;360:279–285. doi: 10.1016/j.bbr.2018.12.023. PubMed DOI

Fisel P., Schaeffeler E., Schwab M. Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy. Clin. Transl. Sci. 2018;11:352–364. doi: 10.1111/cts.12551. PubMed DOI PMC

Pertega-Gomes N., Vizcaíno J.R., Felisbino S., Warren A.Y., Shaw G., Kay J., Whitaker H., Lynch A.G., Fryer L., Neal D.E., et al. Epigenetic and oncogenic regulation of SLC16A7 (MCT2) results in protein over-expression, impacting on signalling and cellular phenotypes in prostate cancer. Oncotarget. 2015;6:21675–21684. doi: 10.18632/oncotarget.4328. PubMed DOI PMC

Ullah M.S., Davies A.J., Halestrap A.P. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J. Biol. Chem. 2006;281:9030–9037. doi: 10.1074/jbc.M511397200. PubMed DOI

Lu W., Huang J., Sun S., Huang S., Gan S., Xu J., Yang M., Xu S., Jiang X. Changes in lactate content and monocarboxylate transporter 2 expression in Aβ25–35-treated rat model of Alzheimer’s disease. Neurol. Sci. 2015;36:871–876. doi: 10.1007/s10072-015-2087-3. PubMed DOI

Daniele L.L., Sauer B., Gallagher S.M., Pugh E.N., Jr., Philp N.J. Altered visual function in monocarboxylate transporter 3 (Slc16a8) knockout mice. Am. J. Physiol. Cell Physiol. 2008;295:C451–C457. doi: 10.1152/ajpcell.00124.2008. PubMed DOI PMC

Gallagher-Colombo S., Maminishkis A., Tate S., Grunwald G.B., Philp N.J. Modulation of MCT3 Expression during Wound Healing of the Retinal Pigment Epithelium. Investig. Ophthalmol. Vis. Sci. 2010;51:5343–5350. doi: 10.1167/iovs.09-5028. PubMed DOI PMC

Zhu S., Goldschmidt-Clermont P.J., Dong C. Inactivation of monocarboxylate transporter MCT3 by DNA methylation in atherosclerosis. Circulation. 2005;112:1353–1361. doi: 10.1161/CIRCULATIONAHA.104.519025. PubMed DOI

Friesema E.C., Grueters A., Biebermann H., Krude H., Moers A., Reeser M., Barrett T.G., Mancilla E.E., Svensson J., Kester M.H.A., et al. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet. 2004;364:1435–1437. doi: 10.1016/S0140-6736(04)17226-7. PubMed DOI

Kersseboom S., Kremers G.-J., Friesema E.C.H., Visser W.E., Klootwijk W., Peeters R.P., Visser T.J. Mutations in MCT8 in Patients with Allan-Herndon-Dudley-Syndrome Affecting Its Cellular Distribution. Mol. Endocrinol. 2013;27:801–813. doi: 10.1210/me.2012-1356. PubMed DOI PMC

Maranduba C.M.C., Friesema E.C.H., Kok F., Kester M.H.A., Jansen J., Sertie A., Passos-Bueno M.R., Visser T.J. Decreased cellular uptake and metabolism in Allan-Herndon-Dudley syndrome (AHDS) due to a novel mutation in the MCT8 thyroid hormone transporter. J. Med. Genet. 2005;43:457–460. doi: 10.1136/jmg.2005.035840. PubMed DOI PMC

Wittmann G., Szabon J., Mohácsik P., Nouriel S.S., Gereben B., Fekete C., Lechan R.M. Parallel Regulation of Thyroid Hormone Transporters OATP1c1 and MCT8 During and After Endotoxemia at the Blood-Brain Barrier of Male Rodents. Endocrinology. 2015;156:1552–1564. doi: 10.1210/en.2014-1830. PubMed DOI PMC

Sun Y., Zhao D., Wang G., Jiang Q., Guo M., Kan Q., He Z., Sun J. A novel oral prodrug-targeting transporter MCT 1: 5-fluorouracil-dicarboxylate monoester conjugates. Asian J. Pharm. Sci. 2019;14:631–639. doi: 10.1016/j.ajps.2019.04.001. PubMed DOI PMC

Cundy K.C., Branch R., Chernov-Rogan T., Dias T., Estrada T., Hold K., Koller K., Liu X., Mann A., Panuwat M., et al. XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: I. Design, synthesis, enzymatic conversion to gabapentin, and transport by intestinal solute transporters. J. Pharmacol. Exp. Ther. 2004;311:315–323. doi: 10.1124/jpet.104.067934. PubMed DOI

Cundy K.C., Annamalai T., Bu L., Vera J.D., Estrela J., Luo W., Shirsat P., Torneros A., Yao F., Zou J., et al. XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid], a novel gabapentin prodrug: II. Improved oral bioavailability, dose proportionality, and colonic absorption compared with gabapentin in rats and monkeys. J. Pharmacol. Exp. Ther. 2004;311:324–333. doi: 10.1124/jpet.104.067959. PubMed DOI

Wang Y., Wang G., Chen H., Sun Y., Sun M., Liu X., Jian W., He Z., Sun J. A facile di-acid mono-amidation strategy to prepare cyclization-activating mono-carboxylate transporter 1-targeting gemcitabine prodrugs for enhanced oral delivery. Int. J. Pharm. 2019;573:118718. doi: 10.1016/j.ijpharm.2019.118718. PubMed DOI

Kim E.S., Deeks E.D. Gabapentin Enacarbil: A Review in Restless Legs Syndrome. Drugs. 2016;76:879–887. doi: 10.1007/s40265-016-0584-1. PubMed DOI

Schweizer U., Johannes J., Bayer D., Braun D. Structure and Function of Thyroid Hormone Plasma Membrane Transporters. Eur. Thyroid J. 2014;3:143–153. doi: 10.1159/000367858. PubMed DOI PMC

Bosshart P.D., Kalbermatter D., Bonetti S., Fotiadis D. Mechanistic basis of L-lactate transport in the SLC16 solute carrier family. Nat. Commun. 2019;10:2649. doi: 10.1038/s41467-019-10566-6. PubMed DOI PMC

Wilson M.C., Meredith D., Bunnun C., Sessions R.B., Halestrap A.P. Studies on the DIDS-binding Site of Monocarboxylate Transporter 1 Suggest a Homology Model of the Open Conformation and a Plausible Translocation Cycle. J. Biol. Chem. 2009;284:20011–20021. doi: 10.1074/jbc.M109.014217. PubMed DOI PMC

Yamaguchi A., Futagi Y., Kobayashi M., Narumi K., Furugen A., Iseki K. Extracellular lysine 38 plays a crucial role in pH-dependent transport via human monocarboxylate transporter 1. Biochim. Biophys. Acta Biomembr. 2020;1862:183068. doi: 10.1016/j.bbamem.2019.183068. PubMed DOI

Futagi Y., Kobayashi M., Narumi K., Furugen A., Iseki K. Homology modeling and site-directed mutagenesis identify amino acid residues underlying the substrate selection mechanism of human monocarboxylate transporters 1 (hMCT1) and 4 (hMCT4) Cell. Mol. Life Sci. 2019;76:4905–4921. doi: 10.1007/s00018-019-03151-z. PubMed DOI PMC

Rahman B., Schneider H.-P., Bröer A., Deitmer J.W., Bröer S. Helix 8 and Helix 10 Are Involved in Substrate Recognition in the Rat Monocarboxylate Transporter MCT1. Biochemistry. 1999;38:11577–11584. doi: 10.1021/bi990973f. PubMed DOI

Galić S., Schneider H.-P., Bröer A., Deitmer J.W., Bröer S. The loop between helix 4 and helix 5 in the monocarboxylate transporter MCT1 is important for substrate selection and protein stability. Biochem. J. 2003;376:413–422. doi: 10.1042/bj20030799. PubMed DOI PMC

Wang N., Jiang X., Zhang S., Zhu A., Yuan Y., Xu H., Lei J., Yan C. Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates. Cell. 2020;184:370–383. doi: 10.1016/j.cell.2020.11.043. PubMed DOI

Groeneweg S., De Souza E.C.L., Meima M.E., Peeters R.P., Visser W.E., Visser T.J. Outward-Open Model of Thyroid Hormone Transporter Monocarboxylate Transporter 8 Provides Novel Structural and Functional Insights. Endocrinology. 2017;158:3292–3306. doi: 10.1210/en.2017-00082. PubMed DOI

Protze J., Braun D., Hinz K.M., Bayer-Kusch D., Schweizer U., Krause G. Membrane-traversing mechanism of thyroid hormone transport by monocarboxylate transporter 8. Cell Mol. Life Sci. 2017;74:2299–2318. doi: 10.1007/s00018-017-2461-9. PubMed DOI PMC

Kinne A., Kleinau G., Hoefig C.S., Grüters A., Köhrle J., Krause G., Schweizer U. Essential Molecular Determinants for Thyroid Hormone Transport and First Structural Implications for Monocarboxylate Transporter 8. J. Biol. Chem. 2010;285:28054–28063. doi: 10.1074/jbc.M110.129577. PubMed DOI PMC

Hagenbuch B., Meier P.J. Organic anion transporting polypeptides of the OATP/SLC21 family: Phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflüg. Arch. 2004;447:653–665. doi: 10.1007/s00424-003-1168-y. PubMed DOI

Roth M., Obaidat A., Hagenbuch B. OATPs, OATs and OCTs: The organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. J. Cereb. Blood Flow Metab. 2012;165:1260–1287. doi: 10.1111/j.1476-5381.2011.01724.x. PubMed DOI PMC

Ronaldson P.T., Davis T.P. Targeted Drug Delivery to Treat Pain and Cerebral Hypoxia. Pharmacol. Rev. 2013;65:291–314. doi: 10.1124/pr.112.005991. PubMed DOI PMC

Gao B., Vavricka S.R., Meier P.J., Stieger B. Differential cellular expression of organic anion transporting peptides OATP1A2 and OATP2B1 in the human retina and brain: Implications for carrier-mediated transport of neuropeptides and neurosteriods in the CNS. Eur. J. Physiol. 2014;467:1481–1493. doi: 10.1007/s00424-014-1596-x. PubMed DOI

Schnell C., Shahmoradi A., Wichert S.P., Mayerl S., Hagos Y., Heuer H., Rossner M.J., Hülsmann S. The multispecific thyroid hormone transporter OATP1C1 mediates cell-specific sulforhodamine 101-labeling of hippocampal astrocytes. Anat. Embryol. 2013;220:193–203. doi: 10.1007/s00429-013-0645-0. PubMed DOI PMC

Schäfer A., zu Schwabedissen H.M., Grube M. Expression and Function of Organic Anion Transporting Polypeptides in the Human Brain: Physiological and Pharmacological Implications. Pharmaceutics. 2021;13:834. doi: 10.3390/pharmaceutics13060834. PubMed DOI PMC

Choi K., Zhuang H., Crain B., Doré S. Expression and localization of prostaglandin transporter in Alzheimer disease brains and age-matched controls. J. Neuroimmunol. 2008;195:81–87. doi: 10.1016/j.jneuroim.2008.01.014. PubMed DOI PMC

Huber R.D., Gao B., Pfändler M.-A.S., Zhang-Fu W., Leuthold S., Hagenbuch B., Folkers G., Meier P.J., Stieger B. Characterization of two splice variants of human organic anion transporting polypeptide 3A1 isolated from human brain. Am. J. Physiol. Physiol. 2007;292:C795–C806. doi: 10.1152/ajpcell.00597.2005. PubMed DOI

Leuthold S., Hagenbuch B., Mohebbi N., Wagner C.A., Meier P.J., Stieger B. Mechanisms of pH-gradient driven transport mediated by organic anion polypeptide transporters. Am. J. Physiol. Cell Physiol. 2009;296:C570–C582. doi: 10.1152/ajpcell.00436.2008. PubMed DOI

Kinzi J., Grube M., Schwabedissen H.E.M.Z. OATP2B1—The underrated member of the organic anion transporting polypeptide family of drug transporters? Biochem. Pharmacol. 2021;188:114534. doi: 10.1016/j.bcp.2021.114534. PubMed DOI

Franke R.M., Scherkenbach L.A., Sparreboom A. Pharmacogenetics of the organic anion transporting polypeptide 1A2. Pharmacogenomics. 2009;10:339–344. doi: 10.2217/14622416.10.3.339. PubMed DOI PMC

Westholm D.E., Salo D.R., Viken K., Rumbley J.N., Anderson G.W. The Blood-Brain Barrier Thyroxine Transporter Organic Anion-Transporting Polypeptide 1c1 Displays Atypical Transport Kinetics. Endocrinology. 2009;150:5153–5162. doi: 10.1210/en.2009-0769. PubMed DOI

Gose T., Nakanishi T., Kamo S., Shimada H., Otake K., Tamai I. Prostaglandin transporter (OATP2A1/SLCO2A1) contributes to local disposition of eicosapentaenoic acid-derived PGE3. Prostaglandins Other Lipid Mediat. 2016;122:10–17. doi: 10.1016/j.prostaglandins.2015.12.003. PubMed DOI

Bakos E., Tusnády G.E., Német O., Patik I., Magyar C., Németh K., Kele P., Özvegy-Laczka C. Synergistic transport of a fluorescent coumarin probe marks coumarins as pharmacological modulators of Organic anion-transporting polypeptide, OATP3A1. Biochem. Pharmacol. 2020;182:114250. doi: 10.1016/j.bcp.2020.114250. PubMed DOI

Bailey D.G., Dresser G.K., Leake B.F., Kim R.B. Naringin is a Major and Selective Clinical Inhibitor of Organic Anion-Transporting Polypeptide 1A2 (OATP1A2) in Grapefruit Juice. Clin. Pharmacol. Ther. 2007;81:495–502. doi: 10.1038/sj.clpt.6100104. PubMed DOI

Morita T., Akiyoshi T., Tsuchitani T., Kataoka H., Araki N., Yajima K., Katayama K., Imaoka A., Ohtani H. Inhibitory Effects of Cranberry Juice and Its Components on Intestinal OATP1A2 and OATP2B1: Identification of Avicularin as a Novel Inhibitor. J. Agric. Food Chem. 2022;70:3310–3320. doi: 10.1021/acs.jafc.2c00065. PubMed DOI

Kalliokoski A., Niemi M. Impact of OATP transporters on pharmacokinetics. J. Cereb. Blood Flow Metab. 2009;158:693–705. doi: 10.1111/j.1476-5381.2009.00430.x. PubMed DOI PMC

Bakos É., Német O., Patik I., Kucsma N., Várady G., Szakács G., Özvegy-Laczka C. A novel fluorescence-based functional assay for human OATP1A2 and OATP1C1 identifies interaction between third-generation P-gp inhibitors and OATP1A2. FEBS J. 2019;287:2468–2485. doi: 10.1111/febs.15156. PubMed DOI

Tikkanen A., Pierrot E., Deng F., Sánchez V.B., Hagström M., Koenderink J.B., Kidron H. Food Additives as Inhibitors of Intestinal Drug Transporter OATP2B1. Mol. Pharm. 2020;17:3748–3758. doi: 10.1021/acs.molpharmaceut.0c00507. PubMed DOI

Unger M.S., Mudunuru J., Schwab M., Hopf C., Drewes G., Nies A.T., Zamek-Gliszczynski M.J., Reinhard F. Clinically Relevant OATP2B1 Inhibitors in Marketed Drug Space. Mol. Pharm. 2019;17:488–498. doi: 10.1021/acs.molpharmaceut.9b00897. PubMed DOI

Chen M., Hu S., Li Y., Gibson A.A., Fu Q., Baker S.D., Sparreboom A. Role of Oatp2b1 in Drug Absorption and Drug-Drug Interactions. Drug Metab. Dispos. 2020;48:420–426. doi: 10.1124/dmd.119.090316. PubMed DOI PMC

Rebello S., Zhao S., Hariry S., Dahlke M., Alexander N., Vapurcuyan A., Hanna I., Jarugula V. Intestinal OATP1A2 inhibition as a potential mechanism for the effect of grapefruit juice on aliskiren pharmacokinetics in healthy subjects. Eur. J. Clin. Pharmacol. 2011;68:697–708. doi: 10.1007/s00228-011-1167-4. PubMed DOI

Kamo S., Nakanishi T., Aotani R., Nakamura Y., Gose T., Tamai I. Impact of FDA-Approved Drugs on the Prostaglandin Transporter OATP2A1/SLCO2A1. J. Pharm. Sci. 2017;106:2483–2490. doi: 10.1016/j.xphs.2017.04.046. PubMed DOI

Lee W., Glaeser H., Smith H., Roberts R.L., Moeckel G.W., Gervasini G., Leake B.F., Kim R.B. Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): Implications for altered drug disposition and central nervous system drug entry. J. Biol. Chem. 2005;280:9610–9617. doi: 10.1074/jbc.M411092200. PubMed DOI

Zhou F., Zheng J., Zhu L., Jodal A., Cui P.H., Wong M., Gurney H., Church W., Murray M. Functional Analysis of Novel Polymorphisms in the Human SLCO1A2 Gene that Encodes the Transporter OATP1A2. AAPS J. 2013;15:1099–1108. doi: 10.1208/s12248-013-9515-1. PubMed DOI PMC

Thompson B.J., Sanchez-Covarrubias L., Slosky L.M., Zhang Y., Laracuente M.-L., Ronaldson P.T. Hypoxia/Reoxygenation Stress Signals an Increase in Organic Anion Transporting polypeptide 1a4 (Oatp1a4) at the Blood–Brain Barrier: Relevance to CNS Drug Delivery. J. Cereb. Blood Flow Metab. 2014;34:699–707. doi: 10.1038/jcbfm.2014.4. PubMed DOI PMC

Nies A.T., Niemi M., Burk O., Winter S., Zanger U.M., Stieger B., Schwab M., Schaeffeler E. Genetics is a major determinant of expression of the human hepatic uptake transporter OATP1B1, but not of OATP1B3 and OATP2B1. Genome Med. 2013;5:1. doi: 10.1186/gm405. PubMed DOI PMC

Tapaninen T., Karonen T., Backman J.T., Neuvonen P.J., Niemi M. SLCO2B1 c.935G>A single nucleotide polymorphism has no effect on the pharmacokinetics of montelukast and aliskiren. Pharm. Genom. 2013;23:19–24. doi: 10.1097/FPC.0b013e32835bac90. PubMed DOI

Schulte R.R., Ho R.H. Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology. Mol. Pharmacol. 2019;95:490–506. doi: 10.1124/mol.118.114314. PubMed DOI PMC

Zhu Q., Liang X., Dai J., Guan X. Prostaglandin transporter, SLCO2A1, mediates the invasion and apoptosis of lung cancer cells via PI3K/AKT/mTOR pathway. Int. J. Clin. Exp. Pathol. 2015;8:9175–9181. PubMed PMC

Mayerl S., Visser T.J., Darras V.M., Horn S., Heuer H. Impact of Oatp1c1 Deficiency on Thyroid Hormone Metabolism and Action in the Mouse Brain. Endocrinology. 2012;153:1528–1537. doi: 10.1210/en.2011-1633. PubMed DOI

Admati I., Wasserman-Bartov T., Tovin A., Rozenblat R., Blitz E., Zada D., Lerer-Goldshtein T., Appelbaum L. Neural Alterations and Hyperactivity of the Hypothalamic–Pituitary–Thyroid Axis in Oatp1c1 Deficiency. Thyroid. 2020;30:161–174. doi: 10.1089/thy.2019.0320. PubMed DOI

Li M., Wang W., Cheng Y., Zhang X., Zhao N., Tan Y., Xie Q., Chai J., Pan Q. Tumor necrosis factor α upregulates the bile acid efflux transporter OATP3A1 via multiple signaling pathways in cholestasis. J. Biol. Chem. 2021;298 doi: 10.1016/j.jbc.2021.101543. PubMed DOI PMC

Choi J.H., Murray J.W., Wolkoff A.W. PDZK1 binding and serine phosphorylation regulate subcellular trafficking of organic anion transport protein 1a1. Am. J. Physiol. Liver Physiol. 2011;300:G384–G393. doi: 10.1152/ajpgi.00500.2010. PubMed DOI PMC

Hänggi E., Grundschober A.F., Leuthold S., Meier P.J., St-Pierre M.V. Functional Analysis of the Extracellular Cysteine Residues in the Human Organic Anion Transporting Polypeptide, OATP2B1. Mol. Pharmacol. 2006;70:806–817. doi: 10.1124/mol.105.019547. PubMed DOI

Meier-Abt F., Mokrab Y., Mizuguchi K. Organic anion transporting polypeptides of the OATP/SLCO superfamily: Identification of new members in nonmammalian species, comparative modeling and a potential transport mode. J. Membr. Biol. 2005;208:213–227. doi: 10.1007/s00232-005-7004-x. PubMed DOI

Betterton R.D., Davis T.P., Ronaldson P.T. Organic Cation Transporter (OCT/OCTN) Expression at Brain Barrier Sites: Focus on CNS Drug Delivery. Handb. Exp. Pharmacol. 2021;266:301–328. doi: 10.1007/164_2021_448. PubMed DOI PMC

Pochini L., Galluccio M., Scalise M., Console L., Indiveri C. OCTN: A Small Transporter Subfamily with Great Relevance to Human Pathophysiology, Drug Discovery, and Diagnostics. SLAS Discov. Adv. Sci. Drug Discov. 2018;24:89–110. doi: 10.1177/2472555218812821. PubMed DOI

Koepsell H., Lips K., Volk C. Polyspecific Organic Cation Transporters: Structure, Function, Physiological Roles, and Biopharmaceutical Implications. Pharm. Res. 2007;24:1227–1251. doi: 10.1007/s11095-007-9254-z. PubMed DOI

Barendt W.M., Wright S.H. The Human Organic Cation Transporter (hOCT2) Recognizes the Degree of Substrate Ionization. J. Biol. Chem. 2002;277:22491–22496. doi: 10.1074/jbc.M203114200. PubMed DOI

Sakata T., Anzai N., Kimura T., Miura D., Fukutomi T., Takeda M., Sakurai H., Endou H. Functional Analysis of Human Organic Cation Transporter OCT3 (SLC22A3) Polymorphisms. J. Pharmacol. Sci. 2010;113:263–266. doi: 10.1254/jphs.09331SC. PubMed DOI

Kerb R., Brinkmann U., Chatskaia N., Gorbunov D., Gorboulev V., Mornhinweg E., Keil A., Eichelbaum M., Koepsell H. Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics. 2002;12:591–595. doi: 10.1097/00008571-200211000-00002. PubMed DOI

Fahrmayr C., Fromm M.F., König J. Hepatic OATP and OCT uptake transporters: Their role for drug-drug interactions and pharmacogenetic aspects. Drug Metab. Rev. 2010;42:380–401. doi: 10.3109/03602530903491683. PubMed DOI

Lin Z., Nelson L., Franke A., Poritz L., Li T.-Y., Wu R., Wang Y., MacNeill C., Thomas N.J., Schreiber S., et al. OCTN1 variant L503F is associated with familial and sporadic inflammatory bowel disease. J. Crohn’s Colitis. 2010;4:132–138. doi: 10.1016/j.crohns.2009.09.003. PubMed DOI

Lahjouji K., Mitchell G.A., Qureshi I.A. Carnitine Transport by Organic Cation Transporters and Systemic Carnitine Deficiency. Mol. Genet. Metab. 2001;73:287–297. doi: 10.1006/mgme.2001.3207. PubMed DOI

Tsuji A. Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems. NeuroRx. 2005;2:54–62. doi: 10.1602/neurorx.2.1.54. PubMed DOI PMC

Nagle M.A., Wu W., Eraly S.A., Nigam S.K. Organic anion transport pathways in antiviral handling in choroid plexus in Oat1 (Slc22a6) and Oat3 (Slc22a8) deficient tissue. Neurosci. Lett. 2013;534:133–138. doi: 10.1016/j.neulet.2012.11.027. PubMed DOI PMC

Saidijam M., Dermani F.K., Sohrabi S., Patching S.G. Efflux proteins at the blood–brain barrier: Review and bioinformatics analysis. Xenobiotica. 2017;48:506–532. doi: 10.1080/00498254.2017.1328148. PubMed DOI

Burckhardt G. Drug transport by Organic Anion Transporters (OATs) Pharmacol. Ther. 2012;136:106–130. doi: 10.1016/j.pharmthera.2012.07.010. PubMed DOI

Montaser A., Markowicz-Piasecka M., Sikora J., Jalkanen A., Huttunen K.M. L-type amino acid transporter 1 (LAT1)-utilizing efflux transporter inhibitors can improve the brain uptake and apoptosis-inducing effects of vinblastine in cancer cells. Int. J. Pharm. 2020;586:119585. doi: 10.1016/j.ijpharm.2020.119585. PubMed DOI

U.S. FDA In Vitro Drug Interaction Studies, Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions, Guidance for Industry. [(accessed on 5 April 2022)];2020 Available online: https://www.fda.gov/media/134582/download.

EMA Guideline on the Investigation of Drug Interactions. 2012. [(accessed on 5 April 2022)]. Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-drug-interactions-revision-1_en.pdf.

VanWert A.L., Gionfriddo M., Sweet D.H. Organic anion transporters: Discovery, pharmacology, regulation and roles in pathophysiology. Biopharm. Drug Dispos. 2009;31:1–71. doi: 10.1002/bdd.693. PubMed DOI

Ciarimboli G. Regulation Mechanisms of Expression and Function of Organic Cation Transporter 1. Front. Pharmacol. 2021;11:2234. doi: 10.3389/fphar.2020.607613. PubMed DOI PMC

Dickens D., Owen A., Alfirevic A., Giannoudis A., Davies A., Weksler B., Romero I., Couraud P.-O., Pirmohamed M. Lamotrigine is a substrate for OCT1 in brain endothelial cells. Biochem. Pharmacol. 2012;83:805–814. doi: 10.1016/j.bcp.2011.12.032. PubMed DOI

Sekhar G.N., Georgian A.R., Sanderson L., Vizcay-Barrena G., Brown R.C., Muresan P., Fleck R., Thomas S.A. Organic cation transporter 1 (OCT1) is involved in pentamidine transport at the human and mouse blood-brain barrier (BBB) PLoS ONE. 2017;12:e0173474. doi: 10.1371/journal.pone.0173474. PubMed DOI PMC

Dos Santos Pereira J.N., Tadjerpisheh S., Abu Abed M., Saadatmand A.R., Weksler B., Romero I., Couraud P.-O., Brockmöller J., Tzvetkov M.V. The Poorly Membrane Permeable Antipsychotic Drugs Amisulpride and Sulpiride Are Substrates of the Organic Cation Transporters from the SLC22 Family. AAPS J. 2014;16:1247–1258. doi: 10.1208/s12248-014-9649-9. PubMed DOI PMC

MacKenzie B., Erickson J.D. Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family. Pflug. Arch. 2004;447:784–795. doi: 10.1007/s00424-003-1117-9. PubMed DOI

Bröer S. The SLC38 family of sodium–amino acid co-transporters. Pflug. Arch. 2014;466:155–172. doi: 10.1007/s00424-013-1393-y. PubMed DOI

Schiöth H.B., Roshanbin S., Hägglund M.G., Fredriksson R. Evolutionary origin of amino acid transporter families SLC32, SLC36 and SLC38 and physiological, pathological and therapeutic aspects. Mol. Asp. Med. 2013;34:571–585. doi: 10.1016/j.mam.2012.07.012. PubMed DOI

Solbu T.T., Bjørkmo M., Berghuis P., Harkany T., Chaudhry F.A. SAT1, a glutamine transporter, is preferentially expressed in GABAergic neurons. Front. Neuroanat. 2010;4:10. doi: 10.3389/neuro.05.001.2010. PubMed DOI PMC

González-González I., Cubelos B., Giménez C., Zafra F. Immunohistochemical localization of the amino acid transporter SNAT2 in the rat brain. Neuroscience. 2005;130:61–73. doi: 10.1016/j.neuroscience.2004.09.023. PubMed DOI

Melone M., Quagliano F., Barbaresi P., Varoqui H., Erickson J.D., Conti F. Localization of the Glutamine Transporter SNAT1 in Rat Cerebral Cortex and Neighboring Structures, With a Note on its Localization in Human Cortex. Cereb. Cortex. 2004;14:562–574. doi: 10.1093/cercor/bhh018. PubMed DOI

Grewal S., Defamie N., Zhang X., Gois S.D., Shawki A., Mackenzie B., Chen C., Varoqui H., Erickson J.D. SNAT2 amino acid transporter is regulated by amino acids of the SLC6 gamma-aminobutyric acid transporter subfamily in neocortical neurons and may play no role in delivering glutamine for glutamatergic transmission. J. Biol. Chem. 2009;284:11224–11236. doi: 10.1074/jbc.M806470200. PubMed DOI PMC

Cubelos B., González-González I.M., Giménez C., Zafra F. Amino acid transporter SNAT5 localizes to glial cells in the rat brain. Glia. 2004;49:230–244. doi: 10.1002/glia.20106. PubMed DOI

Rubio-Aliaga I., Wagner C.A. Regulation and function of the SLC38A3/SNAT3 glutamine transporter. Channels. 2016;10:440–452. doi: 10.1080/19336950.2016.1207024. PubMed DOI PMC

Low S.Y., Taylor P.M., Ahmed A., Pogson C.I., Rennie M.J. Substrate-specificity of glutamine transporters in membrane vesicles from rat liver and skeletal muscle investigated using amino acid analogues. Biochem. J. 1991;278:105–111. doi: 10.1042/bj2780105. PubMed DOI PMC

Hägglund M.G., Hellsten S.V., Bagchi S., Philippot G., Löfqvist E., Nilsson V.C., Almkvist I., Karlsson E., Sreedharan S., Tafreshiha A., et al. Transport of l-Glutamine, l-Alanine, l-Arginine and l-Histidine by the Neuron-Specific Slc38a8 (SNAT8) in CNS. J. Mol. Biol. 2015;427:1495–1512. doi: 10.1016/j.jmb.2014.10.016. PubMed DOI

Hägglund M.G., Sreedharan S., Nilsson V.C., Shaik J.H., Almkvist I.M., Bäcklin S., Wrange Ö., Fredriksson R. Identification of SLC38A7 (SNAT7) Protein as a Glutamine Transporter Expressed in Neurons. J. Biol. Chem. 2011;286:20500–20511. doi: 10.1074/jbc.M110.162404. PubMed DOI PMC

Bagchi S., Baomar H.A., Al-Walai S., Al-Sadi S., Fredriksson R. Histological Analysis of SLC38A6 (SNAT6) Expression in Mouse Brain Shows Selective Expression in Excitatory Neurons with High Expression in the Synapses. PLoS ONE. 2014;9:e95438. doi: 10.1371/journal.pone.0095438. PubMed DOI PMC

Gandasi N., Arapi V., Mickael M., Belekar P., Granlund L., Kothegala L., Fredriksson R., Bagchi S. Glutamine Uptake via SNAT6 and Caveolin Regulates Glutamine–Glutamate Cycle. Int. J. Mol. Sci. 2021;22:1167. doi: 10.3390/ijms22031167. PubMed DOI PMC

Ogura M., Taniura H., Nakamichi N., Yoneda Y. Upregulation of the glutamine transporter through transactivation mediated by camp/protein kinase a signals toward exacerbation of vulnerability to oxidative stress in rat neocortical astrocytes. J. Cell. Physiol. 2007;212:375–385. doi: 10.1002/jcp.21031. PubMed DOI

Ogura M., Nakamichi N., Takano K., Oikawa H., Kambe Y., Ohno Y., Taniura H., Yoneda Y. Functional expression of A glutamine transporter responsive to down-regulation by lipopolysaccharide through reduced promoter activity in cultured rat neocortical astrocytes. J. Neurosci. Res. 2006;83:1447–1460. doi: 10.1002/jnr.20855. PubMed DOI

Rosario F.J., Kanai Y., Powell T.L., Jansson T. Mammalian target of rapamycin signalling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells. J. Physiol. 2013;591:609–625. doi: 10.1113/jphysiol.2012.238014. PubMed DOI PMC

Gu S., Villegas C.J., Jiang J.X. Differential Regulation of Amino Acid Transporter SNAT3 by Insulin in Hepatocytes. J. Biol. Chem. 2005;280:26055–26062. doi: 10.1074/jbc.M504401200. PubMed DOI

Nissen-Meyer L.S.H., Chaudhry F.A. Protein Kinase C Phosphorylates the System N Glutamine Transporter SN1 (Slc38a3) and Regulates Its Membrane Trafficking and Degradation. Front. Endocrinol. 2013;4:138. doi: 10.3389/fendo.2013.00138. PubMed DOI PMC

Uchida Y., Ito K., Ohtsuki S., Kubo Y., Suzuki T., Terasaki T. Major involvement of Na(+) -dependent multivitamin transporter (SLC5A6/SMVT) in uptake of biotin and pantothenic acid by human brain capillary endothelial cells. J. Neurochem. 2015;134:97–112. doi: 10.1111/jnc.13092. PubMed DOI

Salazar K., Martínez F., Pérez-Martín M., Cifuentes M., Trigueros L., Ferrada L., Espinoza F., Saldivia N., Bertinat R., Forman K., et al. SVCT2 Expression and Function in Reactive Astrocytes Is a Common Event in Different Brain Pathologies. Mol. Neurobiol. 2017;55:5439–5452. doi: 10.1007/s12035-017-0762-5. PubMed DOI

Castro M., Caprile T., Astuya-Villalón A., Millán C., Reinicke K., Vera J.C., Vásquez O., Aguayo L.G., Nualart F. High-affinity sodium-vitamin C co-transporters (SVCT) expression in embryonic mouse neurons. J. Neurochem. 2001;78:815–823. doi: 10.1046/j.1471-4159.2001.00461.x. PubMed DOI

Prasad P.D., Wang H., Kekuda R., Fujita T., Fei Y.-J., Devoe L.D., Leibach F.H., Ganapathy V. Cloning and Functional Expression of a cDNA Encoding a Mammalian Sodium-dependent Vitamin Transporter Mediating the Uptake of Pantothenate, Biotin, and Lipoate. J. Biol. Chem. 1998;273:7501–7506. doi: 10.1074/jbc.273.13.7501. PubMed DOI

Nualart F., Mack L., Garcia A., Cisternas P., Bongarzone E.R., Heitzer M., Jara N., Martinez F., Ferrada L., Espinoza F., et al. Vitamin C Transporters, Recycling and the Bystander Effect in the Nervous System: SVCT2 versus Gluts. J. Stem. Cell Res. Ther. 2014;4:209. doi: 10.4172/2157-7633.1000209. PubMed DOI PMC

Zhao Y., Qu B., Wu X., Li X., Liu Q., Jin X., Guo L., Hai L., Wu Y. Design, synthesis and biological evaluation of brain targeting l-ascorbic acid prodrugs of ibuprofen with “lock-in” function. Eur. J. Med. Chem. 2014;82:314–323. doi: 10.1016/j.ejmech.2014.05.072. PubMed DOI

Yue Q., Peng Y., Zhao Y., Lu R., Fu Q., Chen Y., Yang Y., Hai L., Guo L., Wu Y. Dual-targeting for brain-specific drug delivery: Synthesis and biological evaluation. Drug Deliv. 2018;25:426–434. doi: 10.1080/10717544.2018.1431978. PubMed DOI PMC

Wang L., Zhang L., Zhao Y., Fu Q., Xiao W., Lu R., Hai L., Guo L., Wu Y. Design, synthesis, and neuroprotective effects of dual-brain targeting naproxen prodrug. Arch. Pharm. 2018;351:e1700382. doi: 10.1002/ardp.201700382. PubMed DOI

Alam K., Crowe A., Wang X., Zhang P., Ding K., Li L., Yue W. Regulation of Organic Anion Transporting Polypeptides (OATP) 1B1- and OATP1B3-Mediated Transport: An Updated Review in the Context of OATP-Mediated Drug-Drug Interactions. Int. J. Mol. Sci. 2018;19:855. doi: 10.3390/ijms19030855. PubMed DOI PMC

Luo S., Kansara V.S., Zhu X., Mandava N.K., Pal D., Mitra A.K. Functional Characterization of Sodium-Dependent Multivitamin Transporter in MDCK-MDR1 Cells and Its Utilization as a Target for Drug Delivery. Mol. Pharm. 2006;3:329–339. doi: 10.1021/mp0500768. PubMed DOI PMC

Inazu M. Functional Expression of Choline Transporters in the Blood–Brain Barrier. Nutrients. 2019;11:2265. doi: 10.3390/nu11102265. PubMed DOI PMC

Haga T. Molecular properties of the high-affinity choline transporter CHT1. J. Biochem. 2014;156:181–194. doi: 10.1093/jb/mvu047. PubMed DOI

Okuda T., Haga T., Kanai Y., Endou H., Ishihara T., Katsura I. Identification and characterization of the high-affinity choline transporter. Nat. Neurosci. 2000;3:120–125. doi: 10.1038/72059. PubMed DOI

Traiffort E., O’Regan S., Ruat M. The choline transporter-like family SLC44: Properties and roles in human diseases. Mol. Asp. Med. 2013;34:646–654. doi: 10.1016/j.mam.2012.10.011. PubMed DOI

Iwao B., Yara M., Hara N., Kawai Y., Yamanaka T., Nishihara H., Inoue T., Inazu M. Functional expression of choline transporter like-protein 1 (CTL1) and CTL2 in human brain microvascular endothelial cells. Neurochem. Int. 2015;93:40–50. doi: 10.1016/j.neuint.2015.12.011. PubMed DOI

Hirayama B.A., Díez-Sampedro A., Wright E.M. Common mechanisms of inhibition for the Na+/glucose (hSGLT1) and Na+/Cl-/GABA (hGAT1) cotransporters. Br. J. Pharmacol. 2001;134:484–495. doi: 10.1038/sj.bjp.0704274. PubMed DOI PMC

Otto C., Friedrich A., Madunić I.V., Baumeier C., Schwenk R.W., Karaica D., Germer C.-T., Schürmann A., Sabolić I., Koepsell H. Antidiabetic Effects of a Tripeptide That Decreases Abundance of Na+-d-glucose Cotransporter SGLT1 in the Brush-Border Membrane of the Small Intestine. ACS Omega. 2020;5:29127–29139. doi: 10.1021/acsomega.0c03844. PubMed DOI PMC

Tahrani A., Barnett A.H., Bailey C.J. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol. 2013;1:140–151. doi: 10.1016/S2213-8587(13)70050-0. PubMed DOI

Boswell-Casteel R.C., Hays F.A. Equilibrative nucleoside transporters—A review. Nucleosides Nucleotides Nucleic Acids. 2016;36:7–30. doi: 10.1080/15257770.2016.1210805. PubMed DOI PMC

Arcas M.M., Trigueros-Motos L., Casado F.J., Anglada M.P. Physiological and Pharmacological Roles of Nucleoside Transporter Proteins. Nucleosides Nucleotides Nucleic Acids. 2008;27:769–778. doi: 10.1080/15257770802145819. PubMed DOI

Chang C., Swaan P.W., Ngo L.Y., Lum P.Y., Patil S.D., Unadkat J.D. Molecular Requirements of the Human Nucleoside Transporters hCNT1, hCNT2, and hENT1. Mol. Pharmacol. 2004;65:558–570. doi: 10.1124/mol.65.3.558. PubMed DOI

Young J.D., Yao S.Y., Baldwin J.M., Cass C.E., Baldwin S.A. The human concentrative and equilibrative nucleoside transporter families, SLC28 and SLC29. Mol. Asp. Med. 2013;34:529–547. doi: 10.1016/j.mam.2012.05.007. PubMed DOI

Kell D.B., Dobson P.D., Oliver S.G. Pharmaceutical drug transport: The issues and the implications that it is essentially carrier-mediated only. Drug Discov. Today. 2011;16:704–714. doi: 10.1016/j.drudis.2011.05.010. PubMed DOI

Kell D.B. Hitchhiking into the cell. Nat. Chem. Biol. 2020;16:367–368. doi: 10.1038/s41589-020-0489-x. PubMed DOI

Superti-Furga G., Superti-Furga G., Lackner D., Wiedmer T., Ingles-Prieto A., Barbosa B., Girardi E., Goldmann U., Gürtl B., Klavins K., et al. The RESOLUTE consortium: Unlocking SLC transporters for drug discovery. Nat. Rev. Drug Discov. 2020;19:429–430. doi: 10.1038/d41573-020-00056-6. PubMed DOI

Van de Waterbeemd H., Smith D.A., Jones B.C. Lipophilicity in PK design: Methyl, ethyl, futile. J. Comput. Aided Mol. Des. 2001;15:273–286. doi: 10.1023/A:1008192010023. PubMed DOI

Fracassi A., Marangoni M., Rosso P., Pallottini V., Fioramonti M., Siteni S., Segatto M. Statins and the Brain: More than Lipid Lowering Agents? Curr. Neuropharmacol. 2019;17:59–83. doi: 10.2174/1570159X15666170703101816. PubMed DOI PMC