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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Review Article

Potential Regulation Mechanisms of P-gp in the Blood-Brain Barrier in Hypoxia

Author(s): Yidan Ding, Rong Wang*, Jianchun Zhang, Anpeng Zhao, Hui Lu, Wenbin Li, Chang Wang and Xuechun Yuan

Volume 25, Issue 10, 2019

Page: [1041 - 1051] Pages: 11

DOI: 10.2174/1381612825666190610140153

Price: $65

Abstract

The blood-brain barrier (BBB) is a barrier of the central nervous system (CNS), which can restrict the free exchange of substances, such as toxins and drugs, between cerebral interstitial fluid and blood, keeping the relative physiological stabilization. The brain capillary endothelial cells, one of the structures of the BBB, have a variety of ATP-binding cassette transporters (ABC transporters), among which the most widely investigated is Pglycoprotein (P-gp) that can efflux numerous substances out of the brain. The expression and activity of P-gp are regulated by various signal pathways, including tumor necrosis factor-α (TNF-α)/protein kinase C-β (PKC- β)/sphingosine-1-phosphate receptor 1 (S1P), vascular endothelial growth factor (VEGF)/Src kinase, etc. However, it remains unclear how hypoxic signaling pathways regulate the expression and activity of P-gp in brain microvascular endothelial cells. According to previous research, hypoxia affects the expression and activity of the transporter. If the transporter is up-regulated, some drugs enter the brain's endothelial cells and are pumped back into the blood by transporters such as P-gp before they enter the brain tissue, consequently influencing the drug delivery in CNS; if the transporter is down-regulated, the centrally toxic drug would enter the brain tissue and cause serious adverse reactions. Therefore, studying the mechanism of hypoxia-regulating P-gp can provide an important reference for the treatment of CNS diseases with a hypoxia/reoxygenation (H/R) component. This article summarized the mechanism of regulation of P-gp in BBB in normoxia and explored that of hypoxia.

Keywords: P-gp, Blood-brain barrier (BBB), signaling pathway, hypoxia, drug, transcription factor.

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[1]
Hui L, Rong W, Zheng-Ping J, Juan X, Hua X. Effects of High Altitude Exposure on Physiology and Pharmacokinetics. Curr Drug Metab 2016; 17(6): 559-65.
[http://dx.doi.org/10.2174/1389200216666151015113948] [PMID: 26467068]
[2]
Lu H, Wang R, Xiong J, Xie H, Kayser B, Jia ZP. In search for better pharmacological prophylaxis for acute mountain sickness: looking in other directions. Acta Physiol (Oxf) 2015; 214(1): 51-62.
[http://dx.doi.org/10.1111/apha.12490] [PMID: 25778288]
[3]
Chen Y, Zhu ZY, Hong ZY, Chai YF. Research progress of transporter proteins and the transport process of active components of Chinese materia medica across the blood brain barrier. Pharm Care Res 2015; 15(2): 81-7.
[http://dx.doi.org/10.5428/pcar20150201]
[4]
Kingwell K. Drug delivery: New targets for drug delivery across the BBB. Nat Rev Drug Discov 2016; 15(2): 84-5.
[http://dx.doi.org/10.1038/nrd.2016.14] [PMID: 26822834]
[5]
Xu DH, Yan M, Li HD, Fang PF, Liu YW. Influence of P-glycoprotein on brucine transport at the in vitro blood-brain barrier. Eur J Pharmacol 2012; 690(1-3): 68-76.
[http://dx.doi.org/10.1016/j.ejphar.2012.06.032] [PMID: 22749978]
[6]
Banks WA. From blood-brain barrier to blood-brain interface: new opportunities for CNS drug delivery. Nat Rev Drug Discov 2016; 15(4): 275-92.
[http://dx.doi.org/10.1038/nrd.2015.21] [PMID: 26794270]
[7]
McCaffrey G, Davis TP. Physiology and pathophysiology of the blood brain barrier: P-glycoprotein and occludin trafficking as therapeutic targets to optimize CNS drug delivery. J Investig Med 2012; 60(8)
[http://dx.doi.org/10.2310/JIM.0b013e318276de79] [PMID: 23138008]
[8]
Miller DS. Regulation of ABC transporters blood-brain barrier: the good, the bad, and the ugly. Adv Cancer Res 2015; 125: 43-70.
[http://dx.doi.org/10.1016/bs.acr.2014.10.002] [PMID: 25640266]
[9]
Gameiro M, Silva R, Rocha-Pereira C, et al. Cellular Models and In Vitro Assays for the Screening of modulators of P-gp, MRP1 and BCRP. Molecules 2017; 22(4): 1-48.
[http://dx.doi.org/10.3390/molecules22040600] [PMID: 28397762]
[10]
Beaulieu E, Demeule M, Ghitescu L, Béliveau R. P-glycoprotein is strongly expressed in the luminal membranes of the endothelium of blood vessels in the brain. Biochem J 1997; 326(Pt 2): 539-44.
[http://dx.doi.org/10.1042/bj3260539] [PMID: 9291129]
[11]
van Hoppe S, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Breast cancer resistance protein (BCRP-ABCG2) and P-glycoprotein (P-gp-ABCB1) transport afatinib and restrict its oral availability and brain accumulation. Pharmacol Res 2016; 16: 43-50.
[http://dx.doi.org/10.1016/j.phrs.2017.01.035] [PMID: 28288939]
[12]
Chatard M, Puech C, Perek N, Roche F. Hydralazine is a Suitable Mimetic Agent of Hypoxia to Study the Impact of Hypoxic Stress on In Vitro Blood-Brain Barrier Model. Cell Physiol Biochem 2017; 42(4): 1592-602.
[http://dx.doi.org/10.1159/000479399] [PMID: 28738383]
[13]
Hermann DM. Future perspectives for brain pharmacotherapies: implications of drug transport processes at the blood-brain barrier. Ther Adv Neurol Disorder 2008; 1(3): 167-79.
[http://dx.doi.org/10.1177/1756285608097775] [PMID: 21180575]
[14]
Quaegebeur A, Carmeliet P. Oxygen sensing: a common crossroad in cancer and neurodegeneration. Curr Top Microbiol Immunol 2010; 345: 71-103.
[http://dx.doi.org/10.1007/82_2010_83] [PMID: 20582529]
[15]
Peng C, Li WA, Fu P, et al. At low doses ethanol maintains blood-brain barrier (BBB) integrity after hypoxia and reoxygenation: a brain slice study. Neurol Res 2013; 35(8): 790-7.
[http://dx.doi.org/10.1179/1743132813Y.0000000198] [PMID: 23582053]
[16]
Miller DS, Cannon RE. Signaling pathways that regulate basal ABC transporter activity at the blood-brain barrier. Curr Pharm Des 2014; 20(10): 1463-71.
[http://dx.doi.org/10.2174/13816128113199990457] [PMID: 23789954]
[17]
Amin ML. P-glycoprotein Inhibition for Optimal Drug Delivery. Drug Target Insights 2013; 7: 27-34.
[http://dx.doi.org/10.4137/DTI.S12519] [PMID: 24023511]
[18]
Wei H, Lu W, Li M, Zhang Q, Lu S. Concomitance of P-gp/LRP Expression with EGFR Mutations in Exons 19 and 21 in Non-Small Cell Lung Cancers. Yonsei Med J 2016; 57(1): 50-7.
[http://dx.doi.org/10.3349/ymj.2016.57.1.50] [PMID: 26632382]
[19]
Henson JW, Cordon-Cardo C, Posner JB. P-glycoprotein expression in brain tumors. J Neurooncol 1992; 14(1): 37-43.
[http://dx.doi.org/10.1007/BF00170943] [PMID: 1361524]
[20]
Banks WA, Erickson MA. The blood-brain barrier and immune function and dysfunction. Neurobiol Dis 2010; 37(1): 26-32.
[http://dx.doi.org/10.1016/j.nbd.2009.07.031] [PMID: 19664708]
[21]
Wang GY, Wang N, Liao HN. Effects of Muscone on the Expression of P-gp, MMP-9 on Blood-Brain Barrier Model In Vitro. Cell Mol Neurobiol 2015; 35(8): 1105-15.
[http://dx.doi.org/10.1007/s10571-015-0204-8] [PMID: 25976179]
[22]
Rapôso C, Odorissi PA, Oliveira AL, et al. Effect of Phoneutria nigriventer venom on the expression of junctional protein and P-gp efflux pump function in the blood-brain barrier. Neurochem Res 2012; 37(9): 1967-81.
[http://dx.doi.org/10.1007/s11064-012-0817-y] [PMID: 22684283]
[23]
Qosa H, Lichter J, Sarlo M, et al. Astrocytes drive upregulation of the multidrug resistance transporter ABCB1 (P-Glycoprotein) in endothelial cells of the blood-brain barrier in mutant superoxide dismutase 1-linked amyotrophic lateral sclerosis. Glia 2016; 64(8): 1298-313.
[http://dx.doi.org/10.1002/glia.23003] [PMID: 27158936]
[24]
Moriki Y, Suzuki T, Fukami T, Hanano M, Tomono K, Watanabe J. Involvement of P-glycoprotein in blood-brain barrier transport of pentazocine in rats using brain uptake index method. Biol Pharm Bull 2004; 27(6): 932-5.
[http://dx.doi.org/10.1248/bpb.27.932] [PMID: 15187451]
[25]
Hartz AM, Bauer B, Fricker G, Miller DS. Rapid regulation of P-glycoprotein at the blood-brain barrier by endothelin-1. Mol Pharmacol 2004; 66(3): 387-94.
[http://dx.doi.org/10.1124/mol.104.001503] [PMID: 15322229]
[26]
Hartz AM, Bauer B, Fricker G, Miller DS. Rapid modulation of P-glycoprotein-mediated transport at the blood-brain barrier by tumor necrosis factor-alpha and lipopolysaccharide. Mol Pharmacol 2006; 69(2): 462-70.
[http://dx.doi.org/10.1124/mol.105.017954] [PMID: 16278373]
[27]
Pilorget A, Demeule M, Barakat S, Marvaldi J, Luis J, Béliveau R. Modulation of P-glycoprotein function by sphingosine kinase-1 in brain endothelial cells. J Neurochem 2007; 100(5): 1203-10.
[http://dx.doi.org/10.1111/j.1471-4159.2006.04295.x] [PMID: 17316399]
[28]
Cannon RE, Peart JC, Hawkins BT, Campos CR, Miller DS. Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain. Proc Natl Acad Sci USA 2012; 109(39): 15930-5.
[http://dx.doi.org/10.1073/pnas.1203534109] [PMID: 22949658]
[29]
Hawkins BT, Sykes DB, Miller DS. Rapid, reversible modulation of blood-brain barrier P-glycoprotein transport activity by vascular endothelial growth factor. J Neurosci 2010; 30(4): 1417-25.
[http://dx.doi.org/10.1523/JNEUROSCI.5103-09.2010] [PMID: 20107068]
[30]
Pinzón-Daza ML, Salaroglio IC, Kopecka J, et al. The cross-talk between canonical and non-canonical Wnt-dependent pathways regulates P-glycoprotein expression in human blood-brain barrier cells. J Cereb Blood Flow Metab 2014; 34(8): 1258-69.
[http://dx.doi.org/10.1038/jcbfm.2014.100] [PMID: 24896565]
[31]
Chaves CAdS. Mechanisms of regulation of P-glycoprotein and Breast Cancer Resistance Protein at the Blood-Brain Barrier: Focus on the role of morphine, and P-glycoprotein Activation. 2015.
[32]
Avemary J, Salvamoser JD, Peraud A, et al. Dynamic regulation of P-glycoprotein in human brain capillaries. Mol Pharm 2013; 10(9): 3333-41.
[http://dx.doi.org/10.1021/mp4001102] [PMID: 23924183]
[33]
Chan GN, Saldivia V, Yang Y, Pang H, de Lannoy I, Bendayan R. In vivo induction of P-glycoprotein expression at the mouse blood-brain barrier: an intracerebral microdialysis study. J Neurochem 2013; 127(3): 342-52.
[http://dx.doi.org/10.1111/jnc.12344] [PMID: 23777437]
[34]
Pavek P, Cerveny L, Svecova L, et al. Examination of Glucocorticoid receptor α-mediated transcriptional regulation of P-glycoprotein, CYP3A4, and CYP2C9 genes in placental trophoblast cell lines. Placenta 2007; 28(10): 1004-11.
[http://dx.doi.org/10.1016/j.placenta.2007.05.001] [PMID: 17572486]
[35]
Zhong Y, Smart EJ, Weksler B, Couraud PO, Hennig B, Toborek M. Caveolin-1 regulates human immunodeficiency virus-1 Tat-induced alterations of tight junction protein expression via modulation of the Ras signaling. J Neurosci 2008; 28(31): 7788-96.
[http://dx.doi.org/10.1523/JNEUROSCI.0061-08.2008] [PMID: 18667611]
[36]
Cohen AW, Hnasko R, Schubert W, Lisanti MP. Role of caveolae and caveolins in health and disease. Physiol Rev 2004; 84(4): 1341-79.
[http://dx.doi.org/10.1152/physrev.00046.2003] [PMID: 15383654]
[37]
Zhong Y, Hennig B, Toborek M. Intact lipid rafts regulate HIV-1 Tat protein-induced activation of the Rho signaling and upregulation of P-glycoprotein in brain endothelial cells. J Cereb Blood Flow Metab 2010; 30(3): 522-33.
[http://dx.doi.org/10.1038/jcbfm.2009.214] [PMID: 19794400]
[38]
Lu X, Tian Y, Lian X, et al. Integrated systems toxicology approaches identified the possible involvement of ABC transporters pathway in erythromycin estolate-induced liver injury in rat. Food Chem Toxicol 2014; 65: 343-55.
[http://dx.doi.org/10.1016/j.fct.2013.12.050] [PMID: 24412560]
[39]
Chen YL, Yang TY, Chen KC, Wu CL, Hsu SL, Hsueh CM. Hypoxia can impair doxorubicin resistance of non-small cell lung cancer cells by inhibiting MRP1 and P-gp expression and boosting the chemosensitizing effects of MRP1 and P-gp blockers. Cell Oncol (Dordr) 2016; 39(5): 411-33.
[http://dx.doi.org/10.1007/s13402-016-0285-5] [PMID: 27306525]
[40]
Jacob A, Potin S, Saubaméa B, et al. Hypoxia interferes with aryl hydrocarbon receptor pathway in hCMEC/D3 human cerebral microvascular endothelial cells. J Neurochem 2015; 132(4): 373-83.
[http://dx.doi.org/10.1111/jnc.12972] [PMID: 25327972]
[41]
Wang X, Hawkins BT, Miller DS. Aryl hydrocarbon receptor-mediated up-regulation of ATP-driven xenobiotic efflux transporters at the blood-brain barrier. FASEB J 2011; 25(2): 644-52.
[http://dx.doi.org/10.1096/fj.10-169227] [PMID: 21048045]
[42]
Cilek MZ, Hirohata S, Faruk Hatipoglu O, et al. AHR, a novel acute hypoxia-response sequence, drives reporter gene expression under hypoxia in vitro and in vivo. Cell Biol Int 2011; 35(1): 1-8.
[http://dx.doi.org/10.1042/CBI20100290] [PMID: 20795945]
[43]
Kodama S, Negishi M. Sulfotransferase genes: regulation by nuclear receptors in response to xeno/endo-biotics. Drug Metab Rev 2013; 45(4): 441-9.
[http://dx.doi.org/10.3109/03602532.2013.835630] [PMID: 24025090]
[44]
Timsit YE, Negishi M. CAR and PXR: the xenobiotic-sensing receptors. Steroids 2007; 72(3): 231-46.
[http://dx.doi.org/10.1016/j.steroids.2006.12.006] [PMID: 17284330]
[45]
Puech C, Delavenne X, Perek N. The expected characteristics of an in vitro human Blood Brain Barrier model derived from cell lines, for studying how ABC transporters influence drug permeability. J Drug Deliv Sci Technol 2018; 45: 159-67.
[http://dx.doi.org/10.1016/j.jddst.2018.03.002]
[46]
Chan GN, Hoque MT, Cummins CL, Bendayan R. Regulation of P-glycoprotein by orphan nuclear receptors in human brain microvessel endothelial cells. J Neurochem 2011; 118(2): 163-75.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07288.x] [PMID: 21517853]
[47]
Slosky LM, Thompson BJ, Sanchez-Covarrubias L, et al. Acetaminophen modulates P-glycoprotein functional expression at the blood-brain barrier by a constitutive androstane receptor-dependent mechanism. Mol Pharmacol 2013; 84(5): 774-86.
[http://dx.doi.org/10.1124/mol.113.086298] [PMID: 24019224]
[48]
Legendre C, Hori T, Loyer P, et al. Drug-metabolising enzymes are down-regulated by hypoxia in differentiated human hepatoma HepaRG cells: HIF-1alpha involvement in CYP3A4 repression. Eur J Cancer 2009; 45(16): 2882-92.
[http://dx.doi.org/10.1016/j.ejca.2009.07.010] [PMID: 19695866]
[49]
Luo B, Wang R, Li W, et al. Pharmacokinetic changes of norfloxacin based on expression of MRP2 after acute exposure to high altitude at 4300m. Biomed Pharmacother 2017; 89: 1078-85.
[http://dx.doi.org/10.1016/j.biopha.2017.02.092] [PMID: 28292016]
[50]
Copple IM. The Keap1-Nrf2 cell defense pathway--a promising therapeutic target? Adv Pharmacol 2012; 63: 43-79.
[http://dx.doi.org/10.1016/B978-0-12-398339-8.00002-1] [PMID: 22776639]
[51]
Schneider G, Krämer OH. NFκB/p53 crosstalk-a promising new therapeutic target. Biochim Biophys Acta 2011; 1815(1): 90-103.
[http://dx.doi.org/10.1016/j.bbcan.2010.10.003] [PMID: 20951769]
[52]
Bentires-Alj M, Barbu V, Fillet M, et al. NF-kappaB transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene 2003; 22(1): 90-7.
[http://dx.doi.org/10.1038/sj.onc.1206056] [PMID: 12527911]
[53]
Liu Y, Lou G, Wu W, Shi Y, Zheng M, Chen Z. Interferon-α sensitizes HBx-expressing hepatocarcinoma cells to chemotherapeutic drugs through inhibition of HBx-mediated NF-κB activation. Virol J 2013; 10: 168-72.
[http://dx.doi.org/10.1186/1743-422X-10-168] [PMID: 23718853]
[54]
Li W, Li J, Wang R, Xie H, Jia Z. MDR1 will play a key role in pharmacokinetic changes under hypoxia at high altitude and its potential regulatory networks. Drug Metab Rev 2015; 47(2): 191-8.
[http://dx.doi.org/10.3109/03602532.2015.1007012] [PMID: 25639892]
[55]
Wang X, Campos CR, Peart JC, et al. Nrf2 upregulates ATP binding cassette transporter expression and activity at the blood-brain and blood-spinal cord barriers. J Neurosci 2014; 34(25): 8585-93.
[http://dx.doi.org/10.1523/JNEUROSCI.2935-13.2014] [PMID: 24948812]
[56]
Lim JC, Kania KD, Wijesuriya H, et al. Activation of beta-catenin signalling by GSK-3 inhibition increases p-glycoprotein expression in brain endothelial cells. J Neurochem 2008; 106(4): 1855-65.
[http://dx.doi.org/10.1111/j.1471-4159.2008.05537.x] [PMID: 18624906]
[57]
Shen DY, Zhang W, Zeng X, Liu CQ. Inhibition of Wnt/β-catenin signaling downregulates P-glycoprotein and reverses multi-drug resistance of cholangiocarcinoma. Cancer Sci 2013; 104(10): 1303-8.
[http://dx.doi.org/10.1111/cas.12223] [PMID: 23822562]
[58]
Sakamoto A, Suzuki S, Matsumaru T, et al. Correlation of Organic Cation/Carnitine Transporter 1 and Multidrug Resistance-Associated Protein 1 Transport Activities With Protein Expression Levels in Primary Cultured Human Tracheal, Bronchial, and Alveolar Epithelial Cells. J Pharm Sci 2016; 105(2): 876-83.
[http://dx.doi.org/10.1002/jps.24661] [PMID: 26429295]
[59]
Hartz AM, Pekcec A, Soldner EL, Zhong Y, Schlichtiger J, Bauer B. P-gp Protein Expression and Transport Activity in Rodent Seizure Models and Human Epilepsy. Mol Pharm 2017; 14(4): 999-1011.
[http://dx.doi.org/10.1021/acs.molpharmaceut.6b00770] [PMID: 28195743]
[60]
Fang J, Zhou SH, Fan J, Yan SX. Roles of glucose transporter-1 and the phosphatidylinositol 3-kinase/protein kinase B pathway in cancer radioresistance.(review). Mol Med Rep 2015; 11(3): 1573-81.
[http://dx.doi.org/10.3892/mmr.2014.2888] [PMID: 25376370]
[61]
Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased Clearance of CNS B-Amyloid in Alzheimer’s Disease. Science 2010; 330(6012): 1774.
[http://dx.doi.org/10.1126/science.1197623] [PMID: 21148344]
[62]
Newman SA, Pan Y, Short JL, Nicolazzo JA. Assessing the Impact of Lithium Chloride on the Expression of P-Glycoprotein at the Blood-Brain Barrier. J Pharm Sci 2017; 106(9): 2625-31.
[http://dx.doi.org/10.1016/j.xphs.2017.01.013] [PMID: 28093288]
[63]
Fernandes C, Pinto M, Martins C, et al. Development of a PEGylated-Based Platform for Efficient Delivery of Dietary Antioxidants Across the Blood-Brain Barrier. Bioconjug Chem 2018; 29(5): 1677-89.
[http://dx.doi.org/10.1021/acs.bioconjchem.8b00151] [PMID: 29635917]
[64]
Zhang Y, Shen P, Song Y, Lin X. Discussion of the mechanisms of electroacupuncture effect on blood-brain barrier permeability through p-glyco protein. J Zhejiang Univ Sci B 2017; 41(5): 432-6.
[65]
Yang T, Ferrill L, Gallant L, et al. Verapamil and riluzole cocktail liposomes overcome pharmacoresistance by inhibiting P-glycoprotein in brain endothelial and astrocyte cells: A potent approach to treat amyotrophic lateral sclerosis. Eur J Pharm Sci 2018; 120: 30-9.
[http://dx.doi.org/10.1016/j.ejps.2018.04.026] [PMID: 29704642]
[66]
Tome ME, Herndon JM, Schaefer CP, et al. P-glycoprotein traffics from the nucleus to the plasma membrane in rat brain endothelium during inflammatory pain. J Cereb Blood Flow Metab 2016; 36(11): 1913-28.
[http://dx.doi.org/10.1177/0271678X16661728] [PMID: 27466374]
[67]
Schaefer CP, Arkwright NB, Jacobs LM, et al. Chronic morphine exposure potentiates p-glycoprotein trafficking from nuclear reservoirs in cortical rat brain microvessels. PLoS One 2018; 13(2): e0192340.
[http://dx.doi.org/10.1371/journal.pone.0192340] [PMID: 29414996]
[68]
McInerney MP, Volitakis I, Bush AI, Banks WA, Short JL, Nicolazzo JA. Ionophore and Biometal Modulation of P-glycoprotein Expression and Function in Human Brain Microvascular Endothelial Cells. Pharm Res 2018; 35(4): 83.
[http://dx.doi.org/10.1007/s11095-018-2377-6] [PMID: 29508078]
[69]
Otellin VA, Khozhai LI, Tyurenkov IN. Actions of Perinatal Hypoxia on the Structure of the Blood-Brain Barrier in Rats after Administration of Salifen. Neurosci Behav Physiol 2016; 46: 879-81.
[http://dx.doi.org/10.1007/s11055-016-0326-6]
[70]
Crowley E, McDevitt CA, Callaghan R. Generating inhibitors of P-glycoprotein: where to, now? Methods Mol Biol 2010; 596: 405-32.
[http://dx.doi.org/10.1007/978-1-60761-416-6_18] [PMID: 19949934]
[71]
Thomas H. Overcoming Multidrug Resistance in Cancer: An Update on the Clinical Strategy of Inhibiting P-Glycoprotein. Cancer Control 2003; 10: 159-65.
[http://dx.doi.org/10.1177/107327480301000207] [PMID: 12712010]
[72]
Palmeira A, Sousa E, Vasconcelos MH, Pinto MM. Three decades of P-gp inhibitors: skimming through several generations and scaffolds. Curr Med Chem 2012; 19(13): 1946-2025.
[http://dx.doi.org/10.2174/092986712800167392] [PMID: 22257057]
[73]
Abdullahi W, Davis TP, Ronaldson PT. Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery? AAPS J 2017; 19(4): 931-9.
[http://dx.doi.org/10.1208/s12248-017-0081-9] [PMID: 28447295]

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