PET studies on P-glycoprotein function in the blood-brain barrier: How it affects uptake and binding of drugs within the CNS

Current Pharmaceutical Design

Volumn 10, Issue 13, 2004, Pages 1493-1503

  Elsinga, Philip H ^a   Hendrikse, N Harry ^a   Bart, Joost ^a   Vaalburg, Willem ^a   van Waarde, Aren ^a  

^a UNIVERSITY MEDICAL CENTER GRONINGEN   (Netherlands)

Author keywords

ATP binding cassette superfamily of transporters; Carvedilol; CNS drugs; PET; Positron emission tomography; Verapamil

Indexed keywords

AMITRIPTYLINE; ASIMADOLINE; CALCIUM CHANNEL L TYPE; CARAZOLOL; CARBAMAZEPINE; CARFENTANIL; CARRIER PROTEIN; CARVEDILOL; COLCHICINE; COPPER COMPLEX; DAUNORUBICIN; DNA; ELACRIDAR; FELBAMATE; GLYCOPROTEIN P; LAMOTRIGINE; LOPERAMIDE; MORPHINE; MULTIDRUG RESISTANCE PROTEIN; OPIATE ANTAGONIST; ORGANIC ANION TRANSPORTER; PACLITAXEL; PHENOBARBITAL; PHENYTOIN; SEROTONIN ANTAGONIST; TARIQUIDAR; TRACER; UNINDEXED DRUG; VALSPODAR; VERAPAMIL; XENOBIOTIC AGENT;

BLOOD BRAIN BARRIER; CENTRAL NERVOUS SYSTEM; DEGENERATIVE DISEASE; DNA POLYMORPHISM; DOSE RESPONSE; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG BRAIN LEVEL; DRUG DIFFUSION; DRUG DISTRIBUTION; DRUG HALF LIFE; DRUG MECHANISM; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG SCREENING; DRUG UPTAKE; EPILEPSY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; ISOTOPE LABELING; LIPOPHILICITY; MEMBRANE PERMEABILITY; MOLECULAR WEIGHT; MOOD DISORDER; NONHUMAN; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN FUNCTION; PROTEIN TRANSPORT; REVIEW; STRUCTURE ACTIVITY RELATION;

ANIMALS; BLOOD-BRAIN BARRIER; CENTRAL NERVOUS SYSTEM; HUMANS; P-GLYCOPROTEIN; PHARMACEUTICAL PREPARATIONS; PROTEIN BINDING; TOMOGRAPHY, EMISSION-COMPUTED;

EID: 2342436512     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/1381612043384736     Document Type: Review

References (148)

1. Adachi Y, Suzuki H, and Sugiyama Y. Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res 2001; 18: 1660-1668.
2. Adachi Y, Suzuki H, and Sugiyama Y. Quantitative evaluation of the function of small intestinal P-glycoprotein: comparative studies between in situ and in vitro. Pharm Res 2003; 20: 1163-1169.
3. Anglicheau D, Verstuyft C, Laurent-Puig P, Becquemont L, Schlageter MH, Cassinat B, et al. Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients. J Am Soc Nephrol 2003; 14: 1889-1896.
4. Bart J, de Vries EG, Van der Bij W, van der Graaf WT, Sluiter W, Kema IP, et al. [11C]Verapamil PET reveals modulation of P-glycoprotein in the blood-brain barrier by calcineurin blockers in lung transplant recipients. J Nucl Med (submitted)
5. Bart J, Dijkers ECF, Wegman TD, de Vries EG, van der Graaf WT, Groen HJ, et al. New positron emission tomography tracer [11C]carvedilol reveals P-glycoprotein modulation kinetics. Neuroimage (submitted)
6. Bart J, van der Graaf WT, Hendrikse NH, Wegman TD, Willemsen AT, Vaalburg W, et al. Brain irradiation decreases distribution volume of [11C]verapamil in brain metastases. (unpublished work)
7. Bart J, van der Graaf WT, Hollema H, Koopmans J, Vaalburg W, Wegman TD, et al. [11C]Verapamil uptake in tumor xenografts in rat brains can preferentially be increased by modulation of P-glycoprotein expressed in newly formed vessels. Br J Cancer (submitted)
8. Bart J, Willemsen AT, Groen HJ, van der Graaf WT, Wegman T D, Vaalburg W, et al. Quantitative assessment of P-glycoprotein function in the rat blood-brain barrier by distribution volume of [11C]verapamil measured with PET. Neuroimage 2003; 20: 1775-82.
9. Beaulieu E, Demeule M, Ghitescu L, Beliveau 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): 539-544.
10. Bender HM, Dasenbrock J. Brain concentrations of asimadoline in mice: the influence of coadministration of various P-glycoprotein substrates. Int J Clin Pharmacol Ther 1998; 36: 76-79.
11. Boote DJ, Dennis IF, Twentyman PR, Osborne RJ, Laburte C, Hensel S, et al. Phase I study of etoposide with SDZ PSC 833 as a modulator of multidrug resistance in patients with cancer. J Clin Oncol 1996; 14: 610-618.
12. Bradbury MW, Lightman SL. The blood-brain interface. Eye 1990; 4 (Pt 2): 249-254.
13. Brinkmann U. Functional polymorphisms of the human multidrug resistance (MDR1) gene: correlation with P glycoprotein expression and activity in vivo. Novartis Found Symp 2002; 243: 207-210.
14. Brinkmann U, Roots I, Eichelbaum M. Pharmacogenetics of the human drug-transporter gene MDR1: impact of polymorphisms on pharmacotherapy. Drug Discov Today 2001; 6: 835-839.
15. Broxterman HJ, Pinedo HM, Kuiper CM, Kaptein LC, Schuurhuis GJ, Lankelma J. Induction by verapamil of a rapid increase in ATP consumption in multidrug-resistant tumor cells. FASEB J 1988; 2: 2278-2282.
16. Brumme ZL, Dong WW, Chan KJ, Hogg RS, Montaner JS, O'Shaughnessy MV, et al. Influence of polymorphisms within the CX3CR1 and MDR-1 genes on initial antiretroviral therapy response. AIDS 2003; 17: 201-208.
17. Buchwald P, Bodor N. Octanol-water partition: searching for predictive models. Curr Med Chem 1998; 5: 353-380.
18. Butt AM, Jones HC, Abbott NJ. Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study. J Physiol 1990; 429: 47-62.
19. Chishty M, Reichel A, Siva J, Abbott NJ, Begley DJ. Affinity for the P-glycoprotein efflux pump at the blood-brain barrier may explain the lack of CNS side-cffects of modern antihistamines. J Drug Target 2001; 9: 223-228.
20. Cisternino S, Rousselle C, Dagenais C, Scherrmann JM. Screening of multidrug-resistance sensitive drugs by in situ brain perfusion in P-glycoprotein-deficient mice. Pharm Res 2001; 18: 183-190.
21. Cordon Cardo C, O'Brien JP, Casals D, Rittman Grauer L, Biedler JL, Melamed MR, et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 1989; 86: 695-698.
22. Cox DS, Scott KR, Gao H, Eddington ND. Effect of P-glycoprotein on the pharmacokinetics and tissue distribution of enaminone anticonvulsants: analysis by population and physiological approaches. J Pharmacol Exp Ther 2002; 302: 1096-1104.
23. Cox DS, Scott KR, Gao H, Raje S, Eddington ND. Influence of multidrug resistance (MDR) proteins at the blood-brain barrier on the transport and brain distribution of enaminone anticonvulsants. J Pharm Sci 2001; 90: 1540-1552.
24. Dai H, Marbach P, Lemaire M, Hayes M, Elmquist WF. Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. J Pharmacol Exp Ther 2003; 304: 1085-1092.
25. Damiani D, Michieli M, Ermacora A, Russo D, Fanin R, Zaja F, et al. Adjuvant treatment with cyclosporin A increases the toxicity of chemotherapy for remission induction in acute non-lymphocytic leukemia. Leukemia 1998; 12: 1236-1240.
26. Dishino DD, Welch MJ, Kilbourn MR, Raichle ME. Relationship between lipophilicity and brain extraction of C-11-labeled radiopharmaceuticals. J Nucl Med 1983; 24: 1030-1038.
27. Dombrowski SM, Desai SY, Marroni M, Cucullo L, Goodrich K, Bingaman W, et al. Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia 2001; 42: 1501-1506.
28. Doze P, Elsinga PH, Maas B, Van Waarde A, Wegman T, Vaalburg W. Synthesis and evaluation of radiolabeled antagonists for imaging of beta-adrenoceptors in the brain with PET. Neurochem Int 2002; 40: 145-155.
29. Doze P, Van Waarde A, Elsinga PH, Hendrikse NH, Vaalburg W. Enhanced cerebral uptake of receptor ligands by modulation of P-glycoprotein function in the blood-brain barrier. Synapse 2000; 36: 66-74.
30. Doze P, Van Waarde A, Elsinga PH, Loenen Weemaes AM, Willemsen AT, Vaalburg W. Validation of S-1′-[18F]fluorocarazolol for in vivo imaging and quantification of cerebral beta-adrenoceptors. Eur J Pharmacol 1998; 353: 215-226.
31. Drewe J, Gutmann H, Fricker G, Torok M, Beglinger C, Huwyler J. HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Biochem Pharmacol 1999; 57: 1147-1152.
32. Drozdzik M, Bialecka M, Mysliwiec K, Honczarenko K, Stankiewicz J, Sych Z. Polymorphism in the P-glycoprotein drug transporter MDR1 gene: a possible link between environmental and genetic factors in Parkinson's disease. Pharmacogenetics 2003; 13: 259-263.
33. Eckelman WC. Sensitivity of new radiopharmaceuticals. Nucl Med Biol 1998; 25: 169-173.
34. Edwards JE, Brouwer KR, McNamara PJ. GF120918, a P-glycoprotein modulator, increases the concentration of unbound amprenavir in the central nervous system in rats. Antimicrob Agents Chemother 2002; 46: 2284-2286.
35. Elsinga PH, Franssen EJ, Hendrikse NH, Fluks L, Weemaes AM, van der Graaf WT, et al. Carbon-11-labeled daunorubicin and verapamil for probing P-glycoprotein in tumors with PET. J Nucl Med 1996; 37: 1571-1575.
36. Eriks-Fluks E, Elsinga PH, Hendrikse NH, Franssen EJ, Vaalburg W. Enzymatic synthesis of [4-methoxy-11C]daunorubicin for functional imaging of P-glycoprotein with PET. Appl Radiat Isot 1998; 49: 811-813.
37. Fromm MF. The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans. Adv Drug Deliv Rev 2002; 54: 1295-1310.
38. Furuno T, Landi MT, Ceroni M, Caporaso N, Bernucci I, Nappi G, et al. Expression polymorphism of the blood-brain barrier component P-glycoprotein (MDR1) in relation to Parkinson's disease. Pharmacogenetics 2002; 12: 529-534.
39. Gao B, Stieger B, Noe B, Fritschy JM, Meier PJ. Localization of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroid plexus epithelium of rat brain. J Histochem Cytochem 1999; 47: 1255-1264.
40. Golden PL, Pardridge WM. Brain microvascular P-glycoprotein and a revised model of multidrug resistance in brain. Cell Mol Neurobiol 2000; 20: 165-181.
41. Habgood MD, Begley DJ, Abbott NJ. Determinants of passive drug entry into the central nervous system. Cell Mol Neurobiol 2000; 20: 231-253.
42. Hagenbuch B, Gao B, Meier PJ. Transport of xenobiotics across the blood-brain barrier. News Physiol Sci 2002; 17: 231-234.
43. Hendrikse NH, de Vries EG, Eriks-Fluks L, van der Graaf WT, Hospers GA, Willemsen AT, et al. A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier. Cancer Res 1999; 59: 2411-2416.
44. Hendrikse NH, Dijkers ECF, Wegman T, Vaalburg W, Willemsen AT. Quantitative monitoring of P-glycoprotein function in vivo with 11C-carvedilol and PET. J Nucl Med 2001; 42: 279P (abstract)
45. Hendrikse NH, Franssen EJ, van der Graaf WT, Vaalburg W, de Vries EG. Visualization of multidrug resistance in vivo. Eur J Nucl Med 1999; 26: 283-293.
46. Hendrikse NH, Schinkel AH, de Vries EG, Fluks E, van der Graaf WT, Willemsen AT, et al. Complete in vivo reversal of P-glycoprotein pump function in the blood-brain barrier visualized with positron emission tomography. Br J Pharmacol 1998; 124: 1413-1418.
47. Hendrikse NH, Vaalburg W. Dynamics of multidrug resistance: P-glycoprotein analyses with positron emission tomography. Methods 2002; 27: 228-233.
48. Hendrikse NH, Vaalburg W. Imaging of P glycoprotein function in vivo with PET. Novartis Found Symp 2002; 243: 137-145.
49. Hesselink DA, van Schaik RH, van der Heiden IP, van der Werf M, Gregoor PJ, Lindemans J, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 2003; 74: 245-254.
50. Ho GT, Moodie FM, Satsangi J. Multidrug resistance 1 gene (P-glycoprotein 170): an important determinant in gastrointestinal disease? Gut 2003; 52: 759-766.
51. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97: 3473-3478.
52. Huai-Yun H, Secrest DT, Mark KS, Carney D, Brandquist C, Elmquist WF, et al. Expression of multidrug resistance-associated protein (MRP) in brain microvessel endothelial cells. Biochem Biophys Res Commun 1998; 243: 816-820.
53. Huisman MT, Smit JW, Crommentuyn KM, Zelcer N, Wiltshire HR, Beijnen JH, et al. Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs. AIDS 2002; 16: 2295-2301.
54. Huisman MT, Smit JW, Wiltshire HR, Beijnen JH, Schinkel AH. Assessing safety and efficacy of directed P-glycoprotein inhibition to improve the pharmacokinetic properties of saquinavir coadministered with ritonavir. J Pharmacol Exp Ther 2003; 304: 596-602.
55. Illmer T, Schuler US, Thiede C, Schwarz UI, Kim RB, Gotthard S, et al. MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res 2002; 62: 4955-4962.
56. Imbert F, Jardin M, Fernandez C, Gantier JC, Dromer F, Baron G, et al. Effect of efflux inhibition on brain uptake of itraconazole in mice infected with Cryptococcus neoformans. Drug Metab Dispos 2003; 31: 319-325.
57. Janzer RC. The blood-brain barrier: cellular basis. J Inherit Metab Dis 1993; 16: 639-647.
58. Janzer RC, Raff MC. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 1987; 325: 253-257.
59. Jette L, Beliveau R. P-glycoprotein is strongly expressed in brain capillaries. Adv Exp Med Biol 1993; 331: 121-125.
60. Jette L, Murphy GF, Leclerc JM, Beliveau R. Interaction of drugs with P-glycoprotein in brain capillaries. Biochem Pharmacol 1995; 50: 1701-1709.
61. Jette L, Tetu B, Beliveau R. High levels of P-glycoprotein detected in isolated brain capillaries. Biochim Biophys Acta 1993; 1150: 147-154.
62. Jonker JW, Wagenaar E, van Deemter L, Gottschlich R, Bender HM, Dasenbrock J, et al. Role of blood-brain barrier P-glycoprotein in limiting brain accumulation and sedative side-effects of asimadoline, a peripherally acting analgaesic drug. Br J Pharmacol 1999; 127: 43-50.
63. Jonsson O, Behnam-Motlagh P, Persson M, Henriksson R, Grankvist K. Increase in doxorubicin cytotoxicity by carvedilol inhibition of P-glycoprotein activity. Biochem Pharmacol 1999; 58: 1801-1806.
64. Kafka A, Sauer G, Jaeger C, Grundmann R, Kreienberg R, Zeillinger R. Polymorphism C3435T of the MDR-1 gene predicts response to preoperative chemotherapy in locally advanced breast cancer. Int J Oncol 2003; 22: 1117-1121.
65. Karssen AM, Meijer OC, van der Sandt I, de Boer AG, de Lange EC, De Kloet ER. The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone. J Endocrinol 2002; 175: 251-260.
66. Karssen AM, Meijer OC, van der Sandt I, Lucassen PJ, de Lange EC, de Boer AG, et al. Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain. Endocrinology 2001; 142: 2686-2694.
67. Kawamura K, Kobayashi T, Matsuno K, Ishiwata K. Different brain kinetics of two sigma 1 receptor ligands, [3H](+)-pentazocine and [11C]SA4503, by P-glycoprotein modulation. Synapse 2003; 48: 80-86.
68. Kemper EM, van Zandbergen AE, Cleypool C, Mos HA, Boogerd W, Beijnen JH, et al. Increased penetration of paclitaxel into the brain by inhibition of P-Glycoprotein. Clin Cancer Res 2003; 9: 2849-2855.
69. Klohs WD, SteinkampfRW, Havlick MJ, Jackson RC. Resistance to anthrapyrazoles and anthracyclines in multidrug-resistant P388 murine leukemia cells: reversal by calcium blockers and calmodulin antagonists. Cancer Res 1986; 46: 4352-4356.
70. Kung HF, Stevenson DA, Zhuang ZP, Kung MP, Frederick D, Hurt SD. New 5-HT1A receptor antagonist: [3H]p-MPPF. Synapse 1996; 23: 344-346.
71. Kurata Y, Ieiri I, Kimura M, Morita T, Irie S, Urae A, et al. Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin Pharmacol Ther 2002; 72: 209-219.
72. Kurdziel KA, Kiesewetter DO, Carson RE, Eckelman WC, Herscovitch P. Biodistribution, radiation dose estimates, and in vivo Pgp modulation studies of 18F-paclitaxel in nonhuman primates. J Nucl Med 2003; 44: 1330-1339.
73. Kusuhara H, Suzuki H, Naito M, Tsuruo T, Sugiyama Y. Characterization of efflux transport of organic anions in a mouse brain capillary endothelial cell line. J Pharmacol Exp Ther 1998; 285: 1260-1265.
74. Letrent SP, Pollack GM, Brouwer KR, Brouwer KL. Effects of a potent and specific P-glycoprotein inhibitor on the blood-brain barrier distribution and antinociceptive effect of morphine in the rat. Drug Metab Dispos 1999; 27: 827-834.
75. Levchenko A, Mehta BM, Lee JB, Humm JL, Augensen F, Squire O, et al. Evaluation of 11C-colchicine for PET imaging of multiple drug resistance. J Nucl Med 2000; 41: 493-501.
76. Lewis JS, Dearling JL, Sosabowski JK, Zweit J, Carnochan P, Kelland LR, et al. Copper bis(diphosphine) complexes: radiopharmaceuticals for the detection of multi-drug resistance in tumours by PET. Eur J Nucl Med 2000; 27: 638-646.
77. List AF, Kopecky KJ, Willman CL, Head DR, Persons DL, Slovak ML, et al. Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study. Blood 2001; 98: 3212-3220.
78. Luurtsema G, Molthoff CF, Windhorst AD, Smit JW, Keizer H, Boellaard R, et al. (R)- and (S)-[(11)C]verapamil as PET-tracers for measuring P-glycoprotein function: in vitro and in vivo evaluation. Nucl Med Biol 2003; 30: 747-751.
79. Macphee IA, Fredericks S, Tai T, Syrris P, Carter ND, Johnston A, et al. Tacrolimus pharmacogenetics: polymorphisms associated with expression of cytochrome p4503A5 and P-glycoprotein correlate with dose requirement. Transplantation 2002; 74: 1486-1489.
80. Martin SK, Oduola AM, Milhous WK. Reversal of chloroquine resistance in Plasmodium falciparum by verapamil. Science 1987; 235: 899-901.
81. Matsuoka Y, Okazaki M, Kitamura Y, Taniguchi T. Developmental expression of P-glycoprotein (multidrug resistance gene product) in the rat brain. J Neurobiol 1999; 39: 383-392.
82. Matsuzaki J, Yamamoto C, Miyama T, Takanaga H, Matsuo H, Ishizuka H, et al. Contribution of P-glycoprotein to bunitrolol efflux across blood-brain barrier. Biopharm Drug Dispos 1999; 20: 85-90.
83. Mayer U, Wagenaar E, Dorobek B, Beijnen JH, Borst P, Schinkel AH. Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833. J Clin Invest 1997; 100: 2430-2436.
84. Mealey KL, Bentjen SA, Gay JM, Cantor GH. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 2001; 11: 727-733.
85. Mehta BM, Levchenko A, Rosa E, Kim SW, Winnick S, Zhang JJ, et al. Evaluation of carbon-14-colchicine biodistribution with whole-body quantitative autoradiography in colchicine-sensitive and -resistant xenografts. J Nucl Med 1996; 37: 312-314.
86. Mehta BM, Rosa E, Biedler JL, Larson SM. In vivo uptake of carbon-14-colchicine for identification of tumor multidrug resistance. J Nucl Med 1994; 35: 1179-1184.
87. Mehta BM, Rosa E, Fissekis JD, Bading JR, Biedler JL, Larson SM. In-vivo identification of tumor multidrug resistance with 3H-colchicine. J Nucl Med 1992; 33: 1373-1377.
88. Mickley LA, Lee JS, Weng Z, Zhan Z, Alvarez M, Wilson W, et al. Genetic polymorphism in MDR-1: a tool for examining allelic expression in normal cells, unselected and drug-selected cell lines, and human tumors. Blood 1998; 91: 1749-1756.
89. Mistry P, Stewart AJ, Dangerfield W, Okiji S, Liddle C, Bootle D, et al. In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576. Cancer Res 2001; 61: 749-758.
90. Muller MB, Keck ME, Binder EB, Kresse AE, Hagemeyer TP, Landgraf R, et al. ABCB1 (MDR1)-Type P-Glycoproteins at the Blood-Brain Barrier Modulate the Activity of the Hypothalamic-Pituitary-Adrenocortical System: Implications for Affective Disorder. Neuropsychopharmacology (in press)
91. Neugebauer G, Neubert P. Metabolism of carvedilol in man. Eur J Drug Metab Pharmacokinet 1991; 16: 257-260.
92. Neuhoff S, Langguth P, Dressler C, Andersson TB, Regardh CG, Spahn-Langguth H. Affinities at the verapamil binding site of MDR1-encoded P-glycoprotein: drugs and analogs, stereoisomers and metabolites. Int J Clin Pharmacol Ther 2000; 38: 168-179.
93. Newman MJ, Dixon R, Toyonaga B. OC144-093, a novel P glycoprotein inhibitor for the enhancement of anti-epileptic therapy. Novartis Found Symp 2002; 243: 213-226.
94. Packard AB, Kronauge JF, Barbarics E, Kiani S, Treves ST. Synthesis and biodistribution of a Lipophilic 64Cu-labeled monocationic Copper(II) complex. Nucl Med Biol 2002; 29: 289-294.
95. Passchier J, Lawrie KWM, Bender D, Fellows I, Gee AD. [11C]Loperamide as highly sensitive PET probe for measuring changes in P-glycoprotein functionality. J Label Comp Radiopharm 2003; 46: S94 (abstract).
96. Passchier J, Van Waarde A, Doze P, Elsinga PH, Vaalburg W. Influence of P-glycoprotein on brain uptake of [18F]MPPF in rats. Eur J Pharmacol 2000; 407: 273-280.
97. Pearce HL, Winter MA, Beck WT. Structural characteristics of compounds that modulate P-glycoprotein-associated multidrug resistance. Adv Enzyme Regul 1990; 30: 357-373.
98. Pedley TA, Hirano M. Is refractory epilepsy due to genetically determined resistance to antiepileptic drugs? N Engl J Med 2003; 348: 1480-1482.
99. Pike VW, McCarron JA, Lammerstma AA, Hume SP, Poole K, Grasby PM, et al. First delineation of 5-HT1A receptors in human brain with PET and [11C]WAY-100635. Eur J Pharmacol 1995; 283: R1-R3.
100. Pike VW, McCarron JA, Lammertsma AA, Osman S, Hume SP, Sargent PA, et al. Exquisite delineation of 5-HT1A receptors in human brain with PET and [carbonyl-11 C]WAY-100635. Eur J Pharmacol 1996; 301: R5-R7.
101. Polli JW, Baughman TM, Humphreys JE, Jordan KH, Mote AL, Salisbury JA, et al. P-glycoprotein influences the brain concentrations of cetirizine (Zyrtec(R)), a second-generation non-sedating antihistamine. J Pharm Sci 2003; 92: 2082-2089.
102. Polli JW, Jarrett JL, Studenberg SD, Humphreys JE, Dennis SW, Brouwer KR, et al. Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor. Pharm Res 1999; 16: 1206-1212.
103. Potschka H, Fedrowitz M, Loscher W. P-glycoprotein and multidrug resistance-associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. Neuroreport 2001; 12: 3557-3560.
104. Potschka H, Fedrowitz M, Loscher W. P-Glycoprotein-mediated efflux of phenobarbital, lamotrigine, and felbamate at the blood-brain barrier: evidence from microdialysis experiments in rats. Neurosci Lett 2002; 327: 173-176.
105. Rice A, Michaelis ML, Georg G, Liu Y, Turunen B, Audus KL. Overcoming the blood-brain barrier to taxane delivery for neurodegenerative diseases and brain tumors. J Mol Neurosci 2003; 20: 339-344.
106. Roberts RL, Joyce PR, Mulder RT, Begg EJ, Kennedy MA. A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression. Pharmacogenomics J 2002; 2: 191-196.
107. Rose JM, Peckham SL, Scism JL, Audus KL. Evaluation of the role of P-glycoprotein in ivermectin uptake by primary cultures of bovine brain microvessel endothelial cells. Neurochem Res 1998; 23: 203-209
108. Rowinsky EK, Smith L, Wang YM, Chaturvedi P, Villalona M, Campbell E, et al. Phase I and pharmacokinetic study of paclitaxel in combination with biricodar, a novel agent that reverses multidrug resistance conferred by overexpression of both MDR1 and MRP. J Clin Oncol 1998; 16: 2964-2976.
109. Rubin EH, de Alwis DP, Pouliquen I, Green L, Marder P, Lin Y, et al. A phase I trial of a potent P-glycoprotein inhibitor, Zosuquidar. 3HC1 trihydrochloride (LY335979), administered orally in combination with doxorubicin in patients with advanced malignancies. Clin Cancer Res 2002; 8: 3710-3717.
110. Sakata A, Tamai I, Kawazu K, Deguchi Y, Ohnishi T, Saheki A, et al. In vivo evidence for ATP-dependent and P-glycoprotein-mediated transport of cyclosporin A at the blood-brain barrier. Biochem Pharmacol 1994; 48: 1989-1992.
111. Savolainen J, Edwards JE, Morgan ME, McNamara PJ, Anderson BD. Effects of a P-glycoprotein inhibitor on brain and plasma concentrations of anti-human immunodeficiency virus drugs administered in combination in rats. Drug Metab Dispos 2002; 30: 479-482.
112. Schaefer WH, Politowski J, Hwang B, Dixon F Jr, Goalwin A, Gutzait L, et al. Metabolism of carvedilol in dogs, rats, and mice. Drug Metab Dispos 1998; 26: 958-969.
113. Schinkel AH, Mayer U, Wagenaar E, Mol CA, van Deemter L, Smit JJ, et al. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA 1997; 94: 4028-4033.
114. Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77: 491-502.
115. Schinkel AH, Wagenaar E, Mol CA, van Deemter L. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 1996; 97: 2517-2524.
116. Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 1995; 96: 1698-1705.
117. Schumacher U, Mollgard K. The multidrug-resistance P-glycoprotein (Pgp, MDR1) is an early marker of blood-brain barrier development in the microvessels of the developing human brain. Histochem. Cell Biol 1997; 108: 179-182.
118. Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J. Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem 2003; 46: 1716-1725.
119. Schwab M, Schaeffeler E, Marx C, Fromm MF, Kaskas B, Metzler J, et al. Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology 2003; 124: 26-33.
120. Shiue CY, Shiue GG, Mozley PD, Kung MP, Zhuang ZP, Kim HJ, et al. P-[18F]-MPPF: a potential radioligand for PET studies of 5-HT1A receptors in humans. Synapse 1997; 25: 147-154.
121. Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med 2003; 348: 1442-1448.
122. Siegsmund M, Brinkmann U, Schaffeler E, Weirich G, Schwab M, Eichelbaum M, et al. Association of the P-glycoprotein transporter MDR1(C3435T) polymorphism with the susceptibility to renal epithelial tumors. J Am Soc Nephrol 2002; 13: 1847-1854.
123. Silverman JA. Multidrug-resistance transporters. Pharm Biotechnol 1999; 12: 353-386.
124. Sisodiya SM, Thom M. Widespread upregulation of drug-resistance proteins in fatal human status epilepticus. Epilepsia 2003; 44: 261-264.
125. Smith BJ, Doran AC, McLean S, Tingley FD, III, O'Neill BT, Kajiji SM. P-glycoprotein efflux at the blood-brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists. J Pharmacol Exp Ther 2001; 298: 1252-1259.
126. Sparreboom A, Planting AS, Jewell RC, van der Burg ME, van der Gaast A, de Bruijn P, et al. Clinical pharmacokinetics of doxorubicin in combination with GF120918, a potent inhibitor of MDR1 P-glycoprotein. Anticancer Drugs 1999; 10: 719-728.
127. Talbot PS, Narendran R, Hwang DR, Martinez D, Hackett E, Quadri N, et al. Modulation of brain delivery of the mu opiate receptor agonist loperamide by P-glycoprotein inhibition: A PET study using [11C]carfentanil in the baboon. J Nucl Med 2003; 44 (abstract)
128. Tamai I, Nezu J, Uchino H, Sai Y, Oku A, Shimane M, et al. Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family. Biochem Biophys Res Commun 2000; 273: 251-260.
129. Tamai I, Yamashita J, Kido Y, Ohnari A, Sai Y, Shima Y, et al. Limited distribution of new quinolone antibacterial agents into brain caused by multiple efflux transporters at the blood-brain barrier. J Pharmacol Exp Ther 2000; 295: 146-152.
130. Tishler DM, Weinberg KI, Hinton DR, Barbaro N, Annett GM, Raffel C. MDR1 gene expression in brain of patients with medically intractable epilepsy. Epilepsia 1995; 36: 1-6.
131. Toppmeyer D, Seidman AD, Pollak M, Russell C, Tkaczuk K, Verma S, et al. Safety and efficacy of the multidrug resistance inhibitor Incel (biricodar; VX-710) in combination with paclitaxel for advanced breast cancer refractory to paclitaxel. Clin Cancer Res 2002; 8: 670-678.
132. Tsuji A, Tamai I, Sakata A, Tenda Y, Terasaki T. Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter, P-glycoprotein. Biochem Pharmacol 1993; 46: 1096-1099.
133. Uhr M, Holsboer F, Muller MB. 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 2002; 14: 753-759.
134. Uhr M, Steckler T, Yassouridis A, Holsboer F. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdr1a P-glycoprotein gene disruption. Neuropsychopharmacology 2000; 22: 380-387.
135. Van Waarde A, Visser TJ, Elsinga PH, de Jong B, van der Mark TW, Kraan J, et al. Imaging beta-adrenoceptors in the human brain with (S)-1′-[18F]fluorocarazolol. J Nucl Med 1997; 38: 934-939.
136. van der Sandt I, Vos CM, Nabulsi L, Blom-Roosemalen MC, Voorwinden HH, de Boer AG, et al. Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood - brain barrier. AIDS 2001; 15: 483-491.
137. Vogelgesang S, Cascorbi I, Schroeder E, Pahnke J, Kroemer HK, Siegmund W, et al. Deposition of Alzheimer's beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics 2002; 12: 535-541.
138. Wegman TD, Maas B, Elsinga PH, Vaalburg W. An improved method for the preparation of [11C]verapamil. Appl Radiat Isot 2002; 57: 505-507.
139. Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE. Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther 2003; 305: 197-204.
140. Weiss J, Kerpen CJ, Lindenmaier H, Dormann SM, Haefeli WE. Interaction of antiepileptic drugs with human p-glycoprotein in vitro. J Pharmacol Exp Ther 2003; 307: 262-267.
141. Xu J, Ling EA. Studies of the ultrastructure and permeability of the blood-brain barrier in the developing corpus callosum in postnatal rat brain using electron dense tracers. J Anat 1994; 184 (Pt 2): 227-237.
142. Yamamoto C, Murakami H, Koyabu N, Takanaga H, Matsuo H, Uchiumi T, et al. Contribution of P-glycoprotein to efflux of ramosetron, a 5-HT3 receptor antagonist, across the blood-brain barrier. J Pharm Pharmacol 2002; 54: 1055-1063.
143. Yates CR, Zhang W, Song P, Li S, Gaber AO, Kotb M, et al. The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients. J Clin Pharmacol 2003; 43: 555-564.
144. Zhang W, Mojsilovic-Petrovic J, Andrade MF, Zhang H, Ball M, Stanimirovic DB. Expression and functional characterization of ABCG2 in brain endothelial cells and vessels. FASEB J 2003;
145. Zhang Y, Han H, Elmquist WF, Miller DW. Expression of various multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells. Brain Res 2000; 876: 148-153.
146. Hartvig P, Bergstrom M, Antoni G, Langstrom B. Positron emission tomography and brain monoamine neurotransmission - entries for study of drug interactions. Curr Pharm Design 2002; 8(16): 1417-34.
147. Weiser T. AMPA receptor antagonists with additional mechanisms of action: new opportunities for neuroprotective drugs? Curr Pharm Design 2002; 8(10): 941-51.
148. Wong MG, Tehan BG, Lloyd EJ. Molecular mapping in the CNS. Curr Pharm Design 2002; 8(17): 1547-70.