Abstract
At the blood–brain barrier (BBB) many cellular and dynamic mechanisms influence the cerebral drug metabolism and the drug response. In this review, we focus mainly on the role P-glycoprotein (P-gp) plays at the BBB. This protein is a 170-kDa ATP-dependent drug transport protein, located in the apical membrane of endothelial cells. Utilizing ATP hydrolysis as an energy source, it exports molecules which attempt to pass through the cell membrane from the outside to the inside, protecting cells from toxins and a wide range of substances. We briefly summarize some of the currently available in vivo and in vitro methods to investigate P-gp and its substrates. Hitherto, no chemical characteristic has been discovered that clearly distinguishes substrates from non-substrates of P-gp. We discuss some examples of substrates stressing the diversity of drugs and endogenous substances that relate to P-gp either as a substrate, an inhibitor, an inducer or as a combination of the above. Finally, we discuss genetic polymorphisms of the genes encoding for P-gp and their effects on drug response.
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References
Miller DS (2003) Confocal imaging of xenobiotic transport across the blood-brain barrier. J Exp Zoolog Part A Comp Exp Biol 300:84–90
Ballabh P, Braun A, Nedergaard M (2004) The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16:1–13
De Boer AG, van der Sandt IC, Gaillard PJ (2003) The role of drug transporters at the blood–brain barrier. Annu Rev Pharmacol Toxicol 43:629–656
Schinkel AH, Jonker JW (2003) Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev 55:3–29
Begley DJ (2004) ABC transporters and the blood–brain barrier. Curr Pharm Des 10:1295–1312
Dey S, Gunda S, Mitra AK (2004) Pharmacokinetics of erythromycin in rabbit corneas following single-dose infusion. Role of P-glycoprotein as a barrier to in vivo ocular drug absorption. J Pharmacol Exp Ther 31:246–255
Borst P, Evers R, Kool M, Wijnholds J (2000) A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 92:1295–1302
Kerb R, Hoffmeyer S, Brinkmann U (2001) ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2. Pharmacogenomics 2:51–64
Higgins CF, Gottesman MM (1992) Is the multidrug transporter a flippase? Trends Biochem Sci 17:18–21
Fromm MF (2000) P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther 38:69–74
Eisenblätter T, Galla HJ (2002) A new multidrug resistance protein at the blood–brain barrier. Biochem Biophys Res Commun 293:1273–1278
Eisenblätter T, Huwel S, Galla HJ (2003) Characterisation of the brain multidrug resistance protein (BMDP/ABCG2/BCRP) expressed at the blood–brain barrier. Brain Res 971: 221–231
Lee G, Dallas S, Hong M, Bendayan R (2001) Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol Rev 53:569–596
Demeule M, Régina A, Jodoin J, Laplante A, Dagenais C, Berthelet F, Moghrabi A, Beliveau R (2002) Drug transport to the brain: key roles for the efflux pump P-glycoprotein in the blood–brain barrier. Vascul Pharmacol 38:339–348
Bendayan R, Lee G, Bendayan M (2002) Functional expression and localization of P-glycoprotein at the blood brain barrier. Microsc Res Tech 57:365–380
Drozdzik M, Bialecka M, Mysliwiec K, Honczarenko K, Stankiewicz J, Sych Z (2003) Polymorphism in the P-glycoprotein drug transporter MDR1 gene: a possible link between environmental and genetic factors in Parkinson’s disease. Pharmacogenetics 13:259–263
Vogelgesang S, Cascorbi I, Schroeder E, Pahnke J, Kroemer HK, Siegmund W, Kunert-Keil C, Walker LC, Warzok RW (2002) Deposition of Alzheimer’s beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics 12:535–541
Müller MB, Keck ME, Binder EB, Kresse AE, Hagemeyer TP, Landgraf R, Holsboer F, Uhr M (2003) ABCB1 (MDR1)-type P-glycoproteins at the blood–brain barrier modulate the activity of the hypothalamic–pituitary–adrenocortical system: implications for affective disorder. Neuropsychopharmacology 28:1991–1999
Devault A, Gros P (1990) Two members of the mouse mdr gene family confer multidrug resistance with overlapping but distinct drug specificities. Mol Cell Biol 10:1652–1663
Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1989) Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. J Histochem Cytochem 37:159–164
Demeule M, Labelle M, Régina A, Berthelet F, Béliveau R (2001) Isolation of endothelial cells from brain, lung, and kidney: expression of the multidrug resistance P-glycoprotein isoforms. Biochem Biophys Res Commun 281:827–834
Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood–brain barrier sites. Proc Natl Acad Sci USA 86:695–698
Wijnholds J, de Lange EC, Scheffer GL, van den Berg DJ, Mol CA, van der Valk MA, Schinkel AH, Scheper RJ, Breimer DD, Borst P (2000) Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood–cerebrospinal fluid barrier. J Clin Invest 105:279–285
Tamai I, Tsuji A (2000) Transporter-mediated permeation of drugs across the blood-brain barrier. J Pharm Sci 89:1371–1388
Lin JH (2004) How significant is the role of P-glycoprotein in drug absorption and brain uptake? Drugs Today (Barc) 40:5–22
Marroni M, Marchi N, Cucullo L, Abbott NJ, Signorelli K, Janigro D (2003) Vascular and parenchymal mechanisms in multiple drug resistance: a lesson from human epilepsy. Curr Drug Targets 4:297–304
Leonard GD, Fojo T, Bates SE (2003) The role of ABC transporters in clinical practice. Oncologist 8:411–424
Arima H, Yunomae K, Morikawa T, Hirayama F, Uekama K (2004) Contribution of cholesterol and phospholipids to inhibitory effect of dimethyl-beta-cyclodextrin on efflux function of P-glycoprotein and multidrug resistance-associated protein 2 in vinblastine-resistant Caco-2 cell monolayers. Pharm Res 21:625–634
Tang F, Ouyang H, Yang JZ, Borchardt RT (2004) Bidirectional transport of rhodamine 123 and Hoechst 33342, fluorescence probes of the binding sites on P-glycoprotein, across MDCK-MDR1 cell monolayers. J Pharm Sci 93:1185–1194
Elsinga PH, Hendrikse NH, Bart J, Vaalburg W, van Waarde A (2004) PET Studies on P-glycoprotein function in the blood–brain barrier: how it affects uptake and binding of drugs within the CNS. Curr Pharm Des 10:1493–1503
Hau P, Fabel K, Baumgart U, Rummele P, Grauer O, Bock A, Dietmaier C, Dietmaier W, Dietrich J, Dudel C, Hubner F, Jauch T, Drechsel E, Kleiter I, Wismeth C, Zellner A, Brawanski A, Steinbrecher A, Marienhagen J, Bogdahn U (2004) Pegylated liposomal doxorubicin-efficacy in patients with recurrent high-grade glioma. Cancer 100:1199–1207
Gottesman MM, Hrycyna CA, Schoenlein PV, Germann UA, Pastan I (1995) Genetic analysis of the multidrug transporter. Ann Rev Gen 29:607–649
Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, Mol CA, van der Valk MA, Robanus-Maandag EC, te Riele HP, Berns AJM, Borst P (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs. Cell 77:491–502
Chen C, Liu X, Smith BJ (2003) Utility of Mdr1-gene deficient mice in assessing the impact of P-glycoprotein on pharmacokinetics and pharmacodynamics in drug discovery and development. Curr Drug Metab 4:272–291
Uhr M, Namendorf C, Grauer MT, Rosenhagen M, Ebinger M (2004) P-glycoprotein is a factor in the uptake of dextromethorphan, but not of melperone, into the mouse brain. Evidence for an overlap in substrate specificity between P-gp and CYP2D6. J Psychopharmacol 18:509–515
Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75:13–33
Jansen G, Scheper RJ, Dijkmans BA (2003) Multidrug resistance proteins in rheumatoid arthritis, role in disease-modifying antirheumatic drug efficacy and inflammatory processes: an overview. Scand J Rheumatol 32:325–336
Uhr M, Holsboer F, Müller MB (2002) Penetration of endogenous steroid hormones corticosterone, cortisol, aldosterone and progesterone into the brain is enhanced in mice deficient for both mdr1a and mdr1b P-glycoproteins. J Neuroendocrinol 14:753–759
Uhr M, Grauer MT, Holsboer F (2003) Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption. Biol Psychiatry 54:840–846
Holsboer F (2001) Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord 62:77–91
Pariante CM, Thomas SA, Lovestone S, Makoff A, Kerwin RW (2004) Do antidepressants regulate how cortisol affects the brain? Psychoneuroendocrinology 29:423–447
Mukhopadhyay T, Batsakis JG, Kuo MT (1988) Expression of the mdr (P-glycoprotein) gene in Chinese hamster digestive tracts. J Natl Cancer Inst 80:269–275
Varma MV, Ashokraj Y, Dey CS, Panchagnula R (2003) P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement. Pharmacol Res 48:347–359
Abu-Qare AW, Elmasry E, Abou-Donia MB (2003) A role for P-glycoprotein in environmental toxicology. J Toxicol Environ Health B Crit Rev 6:279–288
Sun J, He ZG, Cheng G, Wang SJ, Hao XH, Zou MJ (2004) Multidrug resistance P-glycoprotein: crucial significance in drug disposition and interaction. Med Sci Monit 10:RA5–RA14
Perloff MD, von Moltke LL, Greenblatt DJ (2004) Ritonavir and dexamethasone induce expression of CYP3A and P-glycoprotein in rats. Xenobiotica 34:133–150
Gimenez F, Fernandez C, Mabondzo A (2004) Transport of HIV protease inhibitors through the blood–brain barrier and interactions with the efflux proteins, P-glycoprotein and multidrug resistance proteins. J Acquir Immune Defic Syndr 36:649–658
Zhu HJ, Liu GQ (2004) Glutamate up-regulates P-glycoprotein expression in rat brain microvessel endothelial cells by an NMDA receptor-mediated mechanism. Life Sci 75:1313–1322
Carson SW, Ousmanou AD, Hoyler SL (2002) Emerging significance of P-glycoprotein in understanding drug disposition and drug interactions in psychopharmacology. Psychopharmacol Bull 36:67–81
Mizuno N, Niwa T, Yotsumoto Y, Sugiyama Y (2003) Impact of drug transporter studies on drug discovery and development. Pharmacol Rev 55:425–461
Woodahl EL, Ho RJ (2004) The role of MDR1 genetic polymorphisms in interindividual variability in P-glycoprotein expression and function. Curr Drug Metab 5:11–19
Grauer MT, Uhr M (2004) P-glycoprotein reduces the ability of amitriptyline metabolites to cross the blood brain barrier in mice after a 10-day administration of amitriptyline. J Psychopharmacol 18:66–74
Fellay J, Marzolini C, Meaden E, Back D, Buclin T, Chave J, Decosterd LA, Furrer H, Opravil M, Pantaleo G, Retelska D, Ruiz L, Schinkel AH, Vernazza P, Eap CB, Telenti A, Swiss HIV Cohort Study (2002) Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 359:30–36
Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, Wood NW, Sisodiya SM (2003) Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med 348:1442–1448
Fredericks S, Holt DW, MacPhee IA (2003) The pharmacogenetics of immunosuppression for organ transplantation: a route to individualization of drug administration. Am J Pharmacogenom 3:291–301
Anglicheau D, Thervet E, Etienne I, Hurault De Ligny B, Le Meur Y, Touchard G, Buchler M, Laurent-Puig P, Tregouet D, Beaune P, Daly A, Legendre C, Marquet P (2004) CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther 75:422–433
Bleiber G, May M, Suarez C, Martinez R, Marzolini C, Egger M, Telenti A; Swiss HIV Cohort Study (2004) MDR1 genetic polymorphism does not modify either cell permissiveness to HIV-1 or disease progression before treatment. J Infect Dis 189:583–586
De Luca V, Mundo E, Trakalo J, Wong GW, Kennedy JL (2003) Investigation of polymorphism in the MDR1 gene and antidepressant-induced mania. Pharmacogenom J 3:297–299
Pauli-Magnus C, Feiner J, Brett C, Lin E, Kroetz DL (2003) No effect of MDR1 C3435T variant on loperamide disposition and central nervous system effects. Clin Pharmacol Ther 74:487–498
Skarke C, Jarrar M, Schmidt H, Kauert G, Langer M, Geisslinger G, Lotsch J (2003) Effects of ABCB1 (multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers. Pharmacogenetics 13:651–660
Rochat B, Baumann P, Audus KL (1999) Transport mechanisms for the antidepressant citalopram in brain microvessel endothelium. Brain Res 831(1–2):229–236
Uhr M, Grauer MT (2003) abcd1ab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice. J Psychiatr Res 37(3):179–185
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Ebinger, M., Uhr, M. ABC drug transporter at the blood–brain barrier. Eur Arch Psychiatry Clin Neurosci 256, 294–298 (2006). https://doi.org/10.1007/s00406-006-0664-4
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DOI: https://doi.org/10.1007/s00406-006-0664-4