A review on the impact of P-glycoprotein on the penetration of drugs into the brain. Focus on psychotropic drugs

European Neuropsychopharmacology

Volumn 18, Issue 3, 2008, Pages 157-169

  Linnet, Kristian ^a   Ejsing, Thomas Broeng ^a  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

Author keywords

Blood brain barrier; Drug drug interactions; Mdr1a 1b knock out mice; P glycoprotein; Psychotropic drugs

Indexed keywords

AMISULPRIDE; ANTIDEPRESSANT AGENT; ANTIHISTAMINIC AGENT; CARDIOVASCULAR AGENT; CHLORPROMAZINE; CYCLOSPORIN A; DIGOXIN; DOMPERIDONE; FLUPENTIXOL; FLUPHENAZINE; FLUVOXAMINE; GLYCOPROTEIN P; HALOPERIDOL; LOPERAMIDE; METHADONE; MORPHINE; MULTIDRUG RESISTANCE PROTEIN; NORCLOZAPINE; OLANZAPINE; OPIATE DERIVATIVE; ORGANIC ANION TRANSPORTER; ORGANIC ANION TRANSPORTER 2; ORGANIC CATION TRANSPORTER; PALIPERIDONE; PROTEINASE INHIBITOR; PSYCHOTROPIC AGENT; QUETIAPINE; QUINIDINE; RISPERIDONE; UNINDEXED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; BLOOD BRAIN BARRIER; CHO CELL; CLINICAL OBSERVATION; CONTROLLED STUDY; DRUG PENETRATION; DRUG PROTEIN BINDING; GENE MUTATION; GENETIC POLYMORPHISM; IN VITRO STUDY; KNOCKOUT MOUSE; MOUSE; NONHUMAN; PHARMACOGENOMICS; PRIORITY JOURNAL; REVIEW; RISK ASSESSMENT; SPECIES DIFFERENCE; STRUCTURE ACTIVITY RELATION; TISSUE DISTRIBUTION;

ANIMALS; BLOOD-BRAIN BARRIER; BRAIN; BRAIN CHEMISTRY; DRUG INTERACTIONS; HUMANS; MICE; P-GLYCOPROTEIN; PSYCHOTROPIC DRUGS; RATS; TISSUE DISTRIBUTION;

EID: 38149073214     PISSN: 0924977X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.euroneuro.2007.06.003     Document Type: Review

References (123)

1. Barrand M.A., Robertson K.J., and von Weikersthal S.F. Comparisons of P-glycoprotein expression in isolated rat brain microvessels and in primary cultures of endothelial cells derived from microvasculature of rat brain, epididymal fat pad and from aorta. FEBS Lett. 374 (1995) 179-183
2. Bauer B., Hartz A.M.S., Fricker G., and Miller D.S. Modulation of P-glycoprotein transport function at the blood-brain barrier. Exp. Biol. Med. 230 (2005) 118-127
3. Beaulieu E., Demeule M., Ghitescu L., and Béliveau R. P-glycoprotein is strongly expressed in the luminal membranes of the endothelium of blood vessels in the brain. Biochem. J. 326 (1997) 539-544
4. Begley D.J. ABC transporters and the blood-brain barrier (review). Curr. Pharm. Des. 10 (2004) 1295-1312
5. Bertilsson, Otani K., Dahl M.L., Nordin C., and Åberg-Wistedt A. Stereoselective efflux of (E)-10-hydroxynortriptyline enantiomers from the cerebrospinal fluid of depressed patients. Pharmacol. Toxicol. 68 (1991) 100-103
6. Bosch I., and Croop J.M. P-glycoprotein structure and evolutionary homologies (review). Cytotechnology 27 (1998) 1-30
7. Boström E., Simonsson U.S.H., and Hammarlund-Udenaes M. Oxycodone pharmacokinetics and pharmacodynamics in the rat in the presence of the P-glycoprotein inhibitor PSC833. J. Pharm. Sci. 94 (2005) 1060-1066
8. Boulton D.W., DeVane C.L., Liston H.L., and Markowitz J.S. In vitro P-glycoprotein affinity for atypical and conventional antipsychotics. Life Sci. 71 (2002) 163-169
9. Brunner M., Langer O., Sunder-Plassmann R., Dobrozensky G., Müller U., Wadsak W., Krcal A., Karch R., Mannhalter C., Dudczak R., Kletter K., Steiner I., Baumgartner C., and Müller M. Influence of functional haplotypes in the drug transporter gene ABCB1 on central nervous system drug distribution in humans. Clin. Pharmacol. Ther. 78 (2005) 182-190
10. Chen Y., Pant A.C., and Simon S.M. P-glycoprotein does not reduce substrate concentration from the extracellular leaflet of the plasma membrane in living cells. Cancer Res. 61 (2001) 7763-7769
11. Choo E.F., Leake B., Wandel C., Imamura H., Wood A.J.J., Wilkinson G.R., and Kim R.B. Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab. Dispos. 28 (2000) 655-660
12. Cisternino S., Rousselle C., Debray M., and Scherrmann J.M. In situ transport of vinblastine and selected P-glycoprotein substrates: implications for drug-drug interactions at the mouse blood-brain barrier. Pharm. Res. 21 (2004) 1382-1389
13. Clinckers R., Smolders I., Meurs A., Ebinger G., and Michotte Y. Quantitative in vivo microdialysis study on the influence of multidrug transporters on the blood-brain barrier passage of oxcarbazepine: concomitant use of hippocampal monoamines as pharmacodynamic markers for the anticonvulsant activity. J. Pharmacol. Exp. Ther. 31 (2005) 725-731
14. Cordon-Cardo C., O'Brien J.P., Boccia J., Casals D., Bertino J.R., and Melamed M.R. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J. Histochem. Cytochem. 38 (1990) 1277-1287
15. Cutler L., Hoves C., Deeks N.J., Buck T.L., and Jeffrey P. Development of a P-glycoprotein knockout model in rodents to define species differences in its functional effect at the blood-brain barrier. J. Pharm. Sci. 95 (2006) 1944-1953
16. Dagenais C., Zong J., Ducharme J., and Pollack G.M. Effect of mdr1a P-glycoprotein gene disruption, gender, and substrate concentration on brain uptake of selected compounds. Pharm. Res. 19 (2001) 957-963
17. De Luca V., Mundo E., Trakalo J., Wong G.W.H., and Kennedy J.L. Investigation of polymorphism in the MDR1 gene and antidepressant-induced mania. Pharmacogenomics J. 3 (2003) 297-299
18. Demeule M., Labelle M., Régina A., Berthelet F., and Béliveau R. Isolation of endothelial cells from brain, lung, and kidney: expression of the multidrug resistance O-glycoprotein isoforms. Biochem. Biophys. Res. Commun. 281 (2001) 827-834
19. Ding R., Tayrouz Y., Riedel K.D., Burhenne J., Weiss J., Mikos G., and Haefeli W. Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers. Clin. Pharmacol. Ther. 76 (2004) 73-84
20. Doran A., Obach R.S., Smith B.J., Hosea N.A., Becker S., et al. The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the mdr1a/1b knockout mouse model. Drug Metab. Dispos. 33 (2005) 165-174
21. Drewe J., Gutmann H., Fricker G., Török M., Beglinger C., and Huwyler J. HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine Analog SDZ PSC 833. Biochem. Pharmacol. 57 (1999) 1147-1152
22. Eap C.B., Broly F., Mino A., Hammig R., Deglon J.J., Uehlinger C., Meili D., Chevalley A.F., Bertschy G., Zullino D., Kosel M., Preisig M., and Baumann P. Cytochrome P450 2D6 genotype and methadone steady-state concentrations. J. Clin. Psychopharmacol. 21 (2001) 229-234
23. Eichelbaum M., Fromm M.F., and Schwab M. Clinical aspects of the MDR1 (ABCB1) gene polymorphism (review). Ther. Drug Monit. 26 (2004) 180-185
24. Ejsing T.B., and Linnet K. Influence of P-glycoprotein inhibition on the distribution of the tricyclic antidepressant nortriptyline over the blood-brain barrier. Hum. Psychopharmacol. 20 (2005) 149-153
25. Ejsing T.B., Pedersen A.D., and Linnet K. P-glycoprotein interaction with risperidone and 9-OH-risperidone studied in vitro, in knock-out mice and in drug-drug interaction experiments. Hum. Psychopharmacol. 20 (2005) 493-500
26. Ejsing T.B., Hasselstrøm J., and Linnet K. The influence of P-glycoprotein on cerebral and hepatic concentrations of nortriptyline. Drug Metab. Drug Interac. 21 (2006) 139-162
27. El Ela A.A., Härtter S., Schmitt U., Hiemke C., Spahn-Langguth H., and Langguth P. Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds - implications for pharmacokinetics of selected substrates. J. Pharm. Pharmacol. 56 (2004) 967-975
28. Ford J.M., and Hait W.N. Pharmacology of drugs that alter multidrug resistance in cancer (review). Pharmacol. Rev. 42 (1990) S155-S199
29. Fromm M.F. Importance of P-glycoprotein at blood-tissue barriers. Trends Pharmacol. Sci. 25 (2004) 423-429
30. Germann U., Willingham M.C., Pastan I., and Gottesman M.M. Expression of the human multidrug transporter in insect cells by a recombinant baculovirus. Biochemistry 29 (1990) 2295-2303
31. Grauer M.T., and Uhr M. 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 (2004) 66-74
32. Hitzl M., Schaeffeler E., Hocher B., Slowinski T., Halle H., Eichelbaum M., Kaufmann P., Fritz P., Fromm M.F., and Schwab M. Variable expression of P-glycoprotein in the human placenta and ist association with mutations of the multidrug resistance 1 gene (MDR1. Pharmacogenetics 14 (2004) 309-318
33. Hoffmeyer S., Burk O., von Rischter O., Arnold H.P., Brockmöller J., Johne A., Cascorbi I., Gerloff T., Roots I., Eichelbaum M., and Brinkmann U. Functional polymophisms 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. U. S. A. 97 (2000) 3473-3478
34. Hugnet C., Cadore J.L., Buronfosse F., Pineau X., Mathet T., and Berny P.J. Loperamide poisoning in the dog. Vet. Hum. Toxicol. 38 (1996) 31-33
35. Härtter S., Hüwel S., Lohmann T., El Ala A.A., Langguth P., Hiemke C., and Galla H.J. How does the benzamide antipsychotic amisulpride get into the brain? - an in vitro approach comparing amisulpride with clozapine. Neuropsychopharmacology 28 (2003) 1916-1922
36. Ibrahim S., Peggins J., Knapton A., Licht T., and Aszalos A. Influence of antipsychotic, antiemetic, and Ca2+ channel blocker drugs on the cellular accumulation of the anticancer drug daunorubicin: P-glycoprotein modulation. J. Pharmacol. Exp. Ther. 295 (2000) 1276-1283
37. Jover F., Cuadrado J.M., Andreu L., and Merino J. Reversible coma caused by risperidone-ritonavir interaction. Clin. Neuropharmacol. 25 (2002) 251-253
38. Juliano R.L., and Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta 455 (1976) 152-162
39. Kalvass J.C., Graff C.L., and Pollack G.M. Use of loperamide as a phenotypic probe of mdr1a status in CF-1 mice. Pharm. Res. 21 (2004) 1867-1870
40. Kandimalla K.K., Curran G.L., Holasek S.S., Gilles E.J., Wengenack T.M., and Poduslo J.F. Pharmacokinetic analysis of the blood-brain barrier transport of 125I-amyloid beta protein 40 in wild-type and Alzheimer's disease transgenic mice (APP,PS1) and its implications for amyloid plaque formation. J. Pharmacol. Exp. Ther. 313 (2005) 1370-1378
41. Kelly D.V., Béïque L.C., and Bowmer M.I. Extrapyramidal symptoms with ritonavir/indinavir plus risperidone. Ann. Pharmacother. 36 (2002) 827-830
42. Kharasch E.D., Hoffer C., and Whittington D. The effect of quinidine, used as a probe for the involvement of P-glycoprotein, on the intestinal absorption and pharmacodynamics of methadone. Br. J. Clin. Pharmacol. 57 (2004) 600-610
43. Kimchi-Sarfaty C., Oh J.M., Kim I.-W., Sauna Z.E., Calcagno A.M., Ambudkar S.V., and Gottesman M.M. A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science 315 (2007) 525-528
44. Kim R.B. Drugs as P-glycoprotein substrates, inhibitors, and inducers (review). Drug Metab. Rev. 34 (2002) 47-54
45. Kim D.W., Kim M., Lee S.K., Kang R., and Lee S.Y. Lack of association between C3435T nucleotide MDR1 genetic polymorphism and multidrug-resistant epilepsy. Seizure 5 (2006) 344-347
46. Komar A.A. SNPs, silent but not invisible. Science 315 (2007) 466-467
47. Kurata Y., Ieri I., Kimura M., Morita T., Irie S., Urae A., Ohdo S., Ohtani H., Sawada Y., Higuchi S., and Otsubo K. Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin. Pharmacol. Ther. 72 (2002) 209-219
48. Kusuhara H., Suzuki H., Terasaki T., Kakee A., Lemaire M., and Sugiyama Y. P-glycoprotein mediates the efflux of quinidine across the blood-brain barrier. J. Pharmacol. Exp. Ther. 283 (1997) 574-580
49. Laika B., Leucht S., and Steimer W. ABCB1 (P-glycoprotein/MDR1) gene G2677T/A sequence variation (polymorphism): lack of association with side effects and therapeutic response in depressed inpatients treated with amitriptyline. Clin. Chem. 52 (2006) 893-895
50. Lazarowski A., Massaro M., Schteinschnaider A., Intruvini S., Sevlever G., and Rabinowicz A. Neuronal MDR1 gene expression and persistent low levels of anticonvulsants in a child with refractory epilepsy. Ther. Drug Monit. 26 (2004) 44-46
51. Lazarowski A., Ramos A.J., Garcia-Rivello H., Brusco A., and Girardi E. Neuronal and glial expression of the multidrug resistance gene product in an experimental epilepsy model. Cell. Mol. Neurobiol. 24 (2004) 77-85
52. Letrent S.P., Pollack G.M., Brouwer K.R., and Brouwer K.L.R. 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. 27 (1999) 827-834
53. Lin J.H., and Yamazaki M. Role of P-glycoprotein in pharmacokinetics - clinical implications. Clin. Pharmacokinet. 42 (2003) 59-98
54. Litman T., Druley T.E., Stein W.D., and Bates S.E. From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance (Review). Cell. Mol. Life Sci. 58 (2001) 931-959
55. Loo T.W., and Clarke D.M. Do drug substrates enter the common drug-binding pocket of P-glycoprotein through "gates". Biochem. Biophys. Res. Commun. 329 (2005) 419-422
56. Lugo M.R., and Sharom F.J. Interaction of LDS-751 with P-glycoprotein and mapping of the location of the R drug binding site. Biochemistry 44 (2005) 643-655
57. Marzolini C., Paus E., Buclin T., and Kim R.B. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance (review). Clin. Pharmacol. Ther. 75 (2004) 13-33
58. Mayer U., Wagenaar E., Beijnen J.H., Smit J.W., Meijer D.K.F., van Asperen J., Borst P., and Schinkel A.H. Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr1a P-glycoprotein. Br. J. Pharmacol. 119 (1996) 1038-1044
59. Mealey K.L., Northrup N.C., and Bentjen S.A. Increased toxicity of P-glycoprotein-substrate chemotherapeutic agents in a dog with the MDR1 deletion mutation associated with ivermectin sensitivity. J. Am. Vet. Med. Assoc. 223 (2003) 1453-1455
60. Mealey K.L., Bentjen S.A., Gay J.M., and Cantor G.H. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 11 (2004) 727-733
61. Miura M., Uno T., Tateishi T., and Suzuki T. Pharmacokinetics of fexofenadine enantiomers in healthy subjects. Chirality 19 (2007) 223-227
62. Murakami H., Takanaga H., Matsuo H., Ohtani H., and Sawada Y. Comparison of blood-brain barrier permeability in mice and rats using in situ brain perfusion technique. Am. J. Physiol, Heart Circ. Physiol. 279 (2000) H1022-H1028
63. Nakamura T., Sakaeda T., Horinouchi M., Tamura T., Aoyama N., Shirakawa T., Matsuo M., Kasuga M., and Okumura K. Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin. Pharmacol. Ther. 71 (2002) 297-303
64. Ott J. Association of genetic loci. Neurology 63 (2004) 955-958
65. Pauli-Magnus C., Feiner J., Brett C., Lin E., and Kroetz D.L. No effect of MDR1 C3435T variant loperamide disposition and central nervous system effects. Clin. Pharmacol. Ther. 74 (2003) 487-498
66. Polli J.W., Wring S.A., Humphreys J.E., Huang L., Morgan J.B., Webster L.O., and Serabjit-Singh C.S. Rational use of in vitro P-glycoprotein assays in drug discovery. J. Pharmacol. Exp. Ther. 299 (2001) 620-628
67. Potschka H., and Löscher W. In vivo evidence for P-glycoprotein-mediated transport of phenytoin at the blood-brain barrier of rats. Epilepsia 42 (2001) 1231-1240
68. Potschka H., Fedrowitz M., and Löscher 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 12 (2001) 3557-3560
69. Potschka H., Fedrowitz M., and Löscher W. P-glycoprotein-mediated efflux of phenobarbital, lamotrigine, and felbamate at the blood-brain barrier: evidence from microdialysis experiments in rats. Neurosci. Lett. 327 (2002) 173-176
70. Potschka H., Baltes S., and Löscher W. Inhibition of multidrug transporters by verapamil or probenicid does not alter blood-brain barrier penetration of levetiracetam in rats. Epilepsy Res. 58 (2004) 85-91
71. Rahi, M., Heikkinen, T., Hartter, S., Hakkola, J., Hakala, K., Wallerman, O., Wadelius, M., Wadelius, C., Laine, K., in press. Placental transfer of quetiapine in relation to P-glycoprotein activity. J. Psychopharmacol. (Electronic publication ahead of print).
72. Rao V.V., Dahlheimer J.L., Bardgett M.E., Snyder A.Z., Finch R.A., Sartorelli A.C., and Piwnica-Worms D. Choroid plexus epithelial expression of MDR1 P-glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 3900-3905
73. Regina A., Koman A., Piciotti M., El Hafny B., Center M.S., Bergmann R., Couraud P.O., and Roux F. Mrp1 multidrug resistance-associated protein and P-glycoprotein expression in rat brain microvessels endothelial cells. J. Neurochem. 71 (1998) 705-715
74. Riou M., Guégnard F., le Vern Y., and Kerboeuf D. Modulation of the multidrug resistance (MDR) system in the nematode Haemochus contortus by changing cholesterol content: effects on resistance to anthelmintics. J. Antimicrob. Chemother. 52 (2003) 180-187
75. Roberts R.L., Joyce P.R., Mulder R.T., Begg E.J., and Kennedy M.A. A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression. Pharmacogenomics J. 2 (2002) 191-196
76. Rochat B., Baumann P., and Audus K.L. Transport mechanisms for the antidepressant citalopram in brain microvessel endothelium. Brain Res. 831 (1999) 229-236
77. Rodriguez M., Ortega I., Soengas I., Suarez E., Lukas J.C., and Calvo R. Effect of P-glycoprotein inhibition on methadone analgesia and brain distribution in the rat. J. Pharm. Pharmacol. 56 (2004) 367-374
78. Romsicki Y., and Sharom F.J. The membrane lipid environment modulates drug interactions with the P-glycoprotein multidrug transporter. Biochemistry 38 (1999) 6887-6896
79. Sadeque A.J.M., Wandel C., He H., Shah S., and Wood A.J.J. Increased drug delivery to the brain by P-glycoprotein inhibition. Clin. Pharmacol. Ther. 68 (2000) 231-237
80. Saeki T., Ueda K., Tanigawara Y., Hori R., and Komano T. P-glycoprotein transports cyclosporine A and FK506. J. Biol. Chem. 268 (1993) 6077-6080
81. Sakaeda T., Nakamura T., and Okumura K. Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs (Review). Pharmacogenomics 4 (2003) 397-410
82. Sartor L.L., Bentjen S.A., Trepanier L., and Mealey K.L. Loperamide toxicity in a Collie with the MDR1 mutation associated with ivermectin sensitivity. J. Vet. Intern. Med. 18 (2004) 117-118
83. Schinkel A.H. The physiological function of drug-transporting P-glycoproteins (Review). Semin. Cancer Biol. 8 (1997) 161-170
84. Schinkel A.H. P-glycoprotein, a gatekeeper in the blood-brain barrier (Review). Adv. Drug Deliv. Rev. 36 (1999) 179-194
85. Schinkel A.H., Smit J.J.M., Beijnen J.H., Wagenaar E., van Deemter L., Mol C.A.A.M., van der Valk M.A., Robanus-Maandag E.C., te Riele H.P.J., Berns A.J.M., and Borst P. 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 (1994) 491-502
86. Schinkel A.H., Mayer U., Wagenaar E., Mol C.A.A.M., van Deemter L., Smit J.J.M., van der Valk M.A., Voordouw A.C., Spits H., van Tellingen O., Zijlmans J.M., Fibbe W.E., and Borst P. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc. Natl. Acad. Sci. U. S. A. 94 (1997) 4028-4033
87. Schmitt U., Abou El-Ela A., Guo L.J., et al. Cyclosporine A (CsA) affects the pharmacodynamics and pharmacokinetics of the atypical antipsychotic amisulpride probably via inhibition of P-glycoprotein (P-gp). J. Neural Transm. 113 (2006) 787-801
88. Shapiro A.B., and Ling V. Transport of LDS-751 from the cytoplasmic leaflet of the plasma membrane by the rhodamine-123-selective site of P-glycoprotein. Eur. J. Biochem. 254 (1998) 181-188
89. Sharom F.J. The P-glycoprotein efflux pump: how does it transport drugs? (Review). J. Membr. Biol. 160 (1997) 161-175
90. Siddiqui A., Kerb R., Weale M.E., Brinkmann U., Smith A., Goldstein D.B., Wood N.W., and Sisodya S.M. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N. Engl. J. Med. 348 (2003) 1442-1448
91. Sills G.J., Kwan P., Butler E., de Lange E.C.M., van den Berg D.J., and Brodie M.J. P-glycoprotein-mediated efflux of antiepileptic drugs: preliminary studies in mdr1a knockout mice. Epilepsy Behav. 3 (2002) 427-432
92. Sills G.J., Mohanraj R., Butler E., McCrindle S., Collier L., Wilson E.A., and Brodie M.J. Lack of association between the C3435T Polymorphism in the human multidrug resistance (MDR1) gene and response to antiepileptic drug treatment. Epilepsia 46 (2005) 643-647
93. Sisodiya S.M., Lin W.R., Harding B.N., Squier M.V., and Thom M. Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy. Brain 125 (2002) 22-31
94. Skarke C., Jarrar M., Erb K., Schmidt H., Geisslinger G., and Lötsch J. Respiratory and miotic effects of morphine in healthy volunteers when P-glycoprotein is blocked by quinidine. Clin. Pharmacol. Ther. 74 (2003) 303-311
95. Sparreboom A., Van Asperen J., Mayer U., Schinkel A.H., Smit J.W., Meijer D.K.F., Borst P., Nooijen W.J., Beijnen J.H., and Van Tellingen O. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc. Natl. Acad. Sci. U. S. A. 94 (1997) 2031-2035
96. Sugawara I., Hamada H., Tsuruo T., and Mori S. Specialized localization of P-glycoprotein recognized by MRK 16 monoclonal antibody in endothelial cells of the brain and the spinal cord. Jpn. J. Cancer Res. 81 (1990) 727-730
97. Szabó D., Szabó Jr. G., Ocsovszki I., Aszalos A., and Molnár J. Anti-psychotic drugs reverse multidrug resistance of tumor cell lines and human AML cells ex-vivo. Cancer Lett. 139 (1999) 115-119
98. Tan N.C.K., Heron S.E., Scheffer I.E., Pelekanos J.T., McMahon J.M., Vears D.F., Mulley J.C., and Berkovic S.F. Failure to confirm association of a polymorphism in ABCB1 with multidrug-resistant epilepsy. Neurology 63 (2004) 1090-1092
99. Tanaka Y., Abe Y., Tsugu A., Takamiya Y., Akatsuka A., Tsuruo T., Yamazaki H., Ueyama Y., Sato O., Tamaoki N., and Nakamura M. Ultrastructural localization of P-glycoprotein on capillary endothelial cells in human gliomas. Virchows Arch. 425 (1994) 133-138
100. Task Force on the Use of Laboratory Tests in Psychiatry. Tricyclic antidepressants - blood level measurements and clinical outcome: an APA task force report. Am. J. Psychiatry 142 (1985) 155-162
101. Thuerauf N., and Fromm M.F. The role of the transporter P-glycoprotein for disposition and effects of centrally acting drugs and for the pathogenesis of CNS diseases. Eur. Arch. Psychiatry Clin. Neurosci. 256 (2006) 281-286
102. Tröger U., Lins H., Scherrmann J.M., Wallesch C.W., and Bode-Böger S.M. Tetraparesis associated with colchicines is probably due to inhibition by verapamil of the P-glycoprotein efflux pump in the blood-brain barrier. BMJ 331 (2005) 613
103. Uhr M., and Grauer M.T. abcb1ab P-glycoprotein is involved in uptake of citalopram and trimipramine into the brain of mice. J. Psychiatr. Res. 37 (2003) 179-185
104. Uhr M., Steckler T., Yassouridis A., and 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 22 (2000) 380-387
105. Uhr M., Holsboer F., and Müller M.B. 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 (2002) 753-759
106. Uhr M., Grauer M.T., and Holsboer F. Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption. Biol. Psychiatry 54 (2003) 840-846
107. Van Asperen J., Schinkel A.H., Beijnen J.H., Nooijen W.J., Borst P., and van Tellingen O. Altered pharmacokinetics of vinblastine in Mdr1a P-glycoprotein-deficient mice. J. Natl. Cancer Inst. 88 (1996) 994-999
108. Van Asperen J., van Tellingen O., and Beijnen J.H. The role of mdr1a P-glycoprotein in the biliary and intestinal secretion of doxorubicin and vinblastine in mice. Drug Metab. Dispos. 28 (2000) 264-267
109. Van der Sandt I.C.J., Vos C.M.P., Nabulsi L., Blom-Roosemalen M.C.M., Voorwinden H.H., de Boer A.G., and Breimer D.D. Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood-brain barrier. AIDS 15 (2001) 483-491
110. Virginento D., Robertson D., Errede M., Benagiano V., Girolamo F., Maiorano E., Roncali L., and Bertossi M. Expression of P-glycoprotein in human cerebral cortex microvessels. J. Histochem. Cytochem. 50 (2002) 1671-1676
111. Volk H.A., Burkhardt K., Potschka H., Chen J., Becker A., and Löscher W. Neuronal expression of the drug efflux transporter P-glycoprotein in the rat hippocampus after limbic seizures. Neuroscience 123 (2004) 751-759
112. Wang E.J., Casciano C.N., Clement R.P., and Johnson W.W. Inhibition of P-glycoprotein transport function by grapefruit juice psoralen. Pharm. Res. 18 (2001) 432-438
113. Wang Z., Hamman M.A., Huang S.M., Lesko L.J., and Hall S.D. Effect of St John's wort on the pharmacokinetics of fexofenadine. Clin. Pharmacol. Ther. 71 (2002) 414-420
114. Wang E.-J., Barecki-Roach M., and Johnson W.W. Quantitative characterization of direct P-glycoprotein inhibition by St John's wort constituents hypericin and hyperforin. J. Pharm. Pharmacol. 56 (2004) 123-128
115. Wang J.S., Ruan Y., Taylor R.M., Donovan J.L., Markowitz J.S., and DeVane C.L. Brain penetration of methadone (R)- and (S)-enantiomers is greatly increased by P-glycoprotein deficiency in the blood-brain barrier of Abcb1a gene knockout mice. Psychopharmacology (Berl) 173 (2004) 132-138
116. Wang J.S., Taylor R., Ruan Y., Donovan J.L., Markowitz J.S., and DeVane C.L. Olanzapine penetration into brain is greater in transgenic Abcb1a P-glycoprotein deficient mice than FVB1 (wild-type) animals. Neuropsychopharmacology 29 (2004) 551-557
117. Wang J.S., Ruan Y., Taylor R.M., Donovan J.L., Markowitz J.S., and DeVane C.L. The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein. Int. J. Neuropsychopharmacol. 7 (2004) 415-419
118. Wang J.S., DeVane C.L., Gibson B.B., Donovan J.L., Markowitz J.S., and Zhu H.J. Population pharmacokinetic analysis of drug-drug interactions among risperidone, buprion, and sertraline in CF1 mice. Psychopharmacology (Berl) 183 (2006) 490-499
119. Warren K.E., Patel M.C., McCully C.M., Montuenga L.M., and Balis F.M. Effect of P-glycoprotein modulation with cyclosprin A on cerebrospinal fluid penetration of doxorubicin in non-human primates. Cancer Chemother. Pharmacol. 45 (2000) 207-212
120. Weiss J., Dormann S.M., Martin-Facklam M., Kerpen C.J., Ketabi-Kiyanvash N., and Haefeli W.E. Inhibition of P-glycoprotein by newer antidepressants. J. Pharmacol. Exp. Ther. 305 (2003) 197-204
121. Yamazaki M., Neway W.E., Ohe T., Chen I.-W., Rowe J.F., Hochman J.H., Chiba M., and Lin J.H. In vitro substrate identification studies for P-glycoprotein-mediated transport: species difference and predictability of in vivo results. J. Pharmacol. Exp. Ther. 296 (2001) 723-735
122. Young A.M., Allen C.E., and Audus K.L. Efflux transporters of the human placenta. Adv. Drug Deliv. Rev. 55 (2003) 125-132
123. Zimprich F., Sunder-Plassmann R., Stogmann E., Gleiss A., Dal-Bianco A., Zimprich A., Plumer S., Baumgartner C., and Mannhalter C. Association of an ABCB1 gene haplotype with pharmacoresistance in temporal lobe epilepsy. Neurology 63 (2004) 1087-1089