Drug efflux transporters in the CNS

Levin, 1980, Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability, J. Med. Chem., 23, 682, 10.1021/jm00180a022 Pardridge, 1998, CNS drug design based on principles of blood–brain barrier transport, J. Neurochem., 70, 1781, 10.1046/j.1471-4159.1998.70051781.x Lee, 2001, Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations, Pharmacol. Rev., 53, 569, 10.1146/annurev.pharmtox.41.1.569 Kusuhara, 2001, Efflux transport systems for drugs at the blood–brain barrier and blood–cerebrospinal fluid barrier (Part 1), Drug. Discov. Today, 6, 150, 10.1016/S1359-6446(00)01632-9 Kusuhara, 2001, Efflux transport systems for drugs at the blood–brain barrier and blood–cerebrospinal fluid barrier (Part 2), Drug. Discov. Today, 6, 206, 10.1016/S1359-6446(00)01643-3 Tanigawara, 2000, Role of P-glycoprotein in drug disposition, Ther. Drug Monit., 22, 137, 10.1097/00007691-200002000-00029 Kusuhara, 2002, Role of transporters in the tissue-selective distribution and elimination of drugs: transporters in the liver, small intestine, brain and kidney, J. Controlled Release, 78, 43, 10.1016/S0168-3659(01)00480-1 Schinkel, 1997, The physiological function of drug transporting P-glycoproteins, Semin. Cancer Biol., 8, 161, 10.1006/scbi.1997.0068 Ayrton, 2001, Role of transport proteins in drug absorption, distribution and excretion, Xenobiotica, 319, 469, 10.1080/00498250110060969 Tamai, 2000, Transporter-mediated permeation of drugs across the blood–brain barrier, J. Pharm. Sci., 89, 1371, 10.1002/1520-6017(200011)89:11<1371::AID-JPS1>3.0.CO;2-D Tsuji, 1999, Carrier-mediated or specialized transport of drugs across the blood–brain barrier, Adv. Drug Deliv. Rev., 36, 277, 10.1016/S0169-409X(98)00084-2 Sugiyama, 1999, Kinetic and biochemical analysis of carrier-mediated efflux of drugs through the blood–brain and blood–cerebrospinal fluid barriers: importance in the drug delivery to the brain, J. Controlled Release, 62, 179, 10.1016/S0168-3659(99)00036-X Taylor, 2002, The impact of efflux transporters in the brain on the development of drugs for CNS disorders, Clin. Pharmacokinet., 41, 81, 10.2165/00003088-200241020-00001 van Asperen, 1997, The functional role of P-glycoprotein in the blood–brain barrier, J. Pharm. Sci., 86, 881, 10.1021/js9701364 Terasaki, 1999, The blood–brain barrier efflux transporters as a detoxifying system for the brain, Adv. Drug Deliv. Rev., 5, 195, 10.1016/S0169-409X(98)00088-X Gao, 2001, Organic anion transport across the choroids plexus, Microsc. Res. Tech., 52, 60, 10.1002/1097-0029(20010101)52:1<60::AID-JEMT8>3.0.CO;2-C Juliano, 1976, A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants, Biochim. Biophys. Acta, 455, 152, 10.1016/0005-2736(76)90160-7 Kartner, 1983, Daunorubicin-resistant Chinese hamster ovary cells expressing multidrug resistance and a cell-surface P-glycoprotein, Cancer Res., 43, 4413 Fromm, 2000, P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs, Int. J. Clin. Pharmacol. Ther., 38, 69, 10.5414/CPP38069 Seelig, 1998, A general pattern for substrate recognition by P-glycoprotein, Eur J. Biochem., 251, 252, 10.1046/j.1432-1327.1998.2510252.x Ambudkar, 1999, Biochemical, cellular, and pharmacological aspects of the multidrug transporter, Annu. Rev. Pharmacol. Toxicol., 39, 361, 10.1146/annurev.pharmtox.39.1.361 Ekins, 2002, Three-dimensional quantitative structure–activity relationships of inhibitors of P-gp, Mol. Pharmacol., 61, 964, 10.1124/mol.61.5.964 Ekins, 2002, Application of three-dimensional quantitative structure–activity relationships of p-glycoprotein inhibitors and substrates, Mol. Pharmacol., 61, 974, 10.1124/mol.61.5.974 Cordon-Cardo, 1989, Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood–brain barrier sites, Proc. Natl. Acad. Sci. USA, 86, 695, 10.1073/pnas.86.2.695 Thiebaut, 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, 10.1177/37.2.2463300 Sugawara, 1990, Expression and functions of P-glycoprotein (mdr1 gene product) in normal and malignant tissues, Acta. Pathol. Jpn., 40, 545 van der Valk, 1990, Distribution of multidrug resistance-associated P-glycoprotein in normal and neoplastic human tissues. Analysis with 3 monoclonal antibodies recognizing different epitopes of the P-glycoprotein molecule, Ann. Oncol., 1, 56, 10.1093/oxfordjournals.annonc.a057676 Becker, 1991, The multidrug-resistance gene MDR1 is expressed in human glial tumors, Acta Neuropathol. (Berl)., 82, 516, 10.1007/BF00293387 Nabors, 1991, Multidrug resistance gene (MDR1) expression in human brain tumors, J. Neurosurg., 75, 941, 10.3171/jns.1991.75.6.0941 Tanaka, 1994, Ultrastructural localization of P-glycoprotein on the capillary endothelial cells in human gliomas, Virchows Arch., 425, 133, 10.1007/BF00230349 Toth, 1996, MDR1 P-glycoprotein is expressed by endothelial cells of newly formed capillaries in human gliomas but is not expressed in the neovasculature of other primary tumors, Am. J. Pathol., 149, 853 Biegel, 1995, Isolation and culture of human brain microvessel endothelial cells for the study of blood–brain barrier properties in vitro, Brain Res., 692, 183, 10.1016/0006-8993(95)00511-N Barrand, 1995, 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, 179, 10.1016/0014-5793(95)01104-M Jette, 1995, Interaction of drugs with P-glycoprotein in brain capillaries, Biochem. Pharmacol., 50, 1701, 10.1016/0006-2952(95)02073-X Hegmann, 1992, Expression and functional activity of P-glycoprotein in cultured cerebral capillary endothelial cells, Cancer Res., 52, 6969 Shirai, 1994, Transport of cyclosporin A across the brain capillary endothelial cell monolayer by P-glycoprotein, Biochim. Biophys. Acta, 1222, 400, 10.1016/0167-4889(94)90047-7 Tsuji, 1992, P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells, Life Sci., 51, 1427, 10.1016/0024-3205(92)90537-Y Tsuji, 1993, Restricted transport of cyclosporin A across the blood–brain barrier by a multidrug transporter, P-glycoprotein, Biochem. Pharmacol., 46, 1096, 10.1016/0006-2952(93)90677-O Jette, 1993, High levels of P-glycoprotein detected in isolated brain capillaries, Biochim. Biophys. Acta, 1150, 147, 10.1016/0005-2736(93)90083-C Beaulieu, 1997, P-glycoprotein is strongly expressed in the luminal membranes of the endothelium of blood vessels in the brain, Biochem. J., 326, 539, 10.1042/bj3260539 Pardridge, 1997, Brain microvascular and astrocyte localization of P-glycoprotein, J. Neurochem., 68, 1278, 10.1046/j.1471-4159.1997.68031278.x Golden, 1999, P-Glycoprotein on astrocyte foot processes of unfixed isolated human brain capillaries, Brain Res., 819, 143, 10.1016/S0006-8993(98)01305-5 Golden, 2000, Brain microvascular P-glycoprotein and a revised model of multidrug resistance in brain, Cell Mol. Neurobiol., 20, 165, 10.1023/A:1007093521681 Lee, 2001, Functional expression of P-glycoprotein in rat brain microglia, J. Pharmacol. Exp. Ther., 299, 204 Murata, 1999, Efflux transport of a new quinolone antibacterial agent, HSR-903, across the blood–brain barrier, J. Pharmacol. Exp. Ther., 290, 51 Cox, 2001, Influence of multidrug resistance (MDR) proteins at the blood–brain barrier on the transport and brain distribution of enaminone anticonvulsants, J. Pharm. Sci., 90, 540, 10.1002/jps.1104 Miller, 2002, Xenobiotic efflux pumps in isolated fish brain capillaries, Am. J. Physiol. Regul. Integr. Comp. Physiol., 282, R191, 10.1152/ajpregu.00305.2001 Chishty, 2001, Affinity for the P-glycoprotein efflux pump at the blood–brain barrier may explain the lack of CNS side-effects of modern antihistamines, J. Drug Target., 9, 223, 10.3109/10611860108997930 Hosoya, 2000, mRNA expression and transport characterization of conditionally immortalized rat brain capillary endothelial cell lines; a new in vitro BBB model for drug targeting, J. Drug Target., 8, 357, 10.3109/10611860008997912 Fontaine, 1996, Use of rhodamine 123 to examine the functional activity of P-glycoprotein in primary cultured brain microvessel endothelial cell monolayers, Life Sci., 59, 521, 10.1016/0024-3205(96)00483-3 Batrakova, 2001, Mechanism of pluronic effect on P-glycoprotein efflux system in blood–brain barrier: contributions of energy depletion and membrane fluidization, J. Pharmacol. Exp. Ther., 299, 483 Fenart, 1998, Inhibition of P-glycoprotein: rapid assessment of its implication in blood–brain barrier integrity and drug transport to the brain by an in vitro model of the blood–brain barrier, Pharm. Res., 15, 993, 10.1023/A:1011913723928 Gaillard, 2000, Astrocytes increase the functional expression of P-glycoprotein in an in vitro model of the blood–brain barrier, Pharm. Res., 17, 1198, 10.1023/A:1026406528530 Megard, 2002, A co-culture-based model of human blood–brain barrier: application to active transport of indinavir and in vivo–in vitro correlation, Brain Res., 927, 153, 10.1016/S0006-8993(01)03337-6 Tatsuta, 1992, Functional involvement of P- glycoprotein in blood–brain barrier, J. Biol. Chem., 267, 20383, 10.1016/S0021-9258(19)88713-6 Decleves, 2000, Functional expression of P-glycoprotein and multidrug resistance-associated protein (Mrp1) in primary cultures of rat astrocytes, J. Neurosci. Res., 60, 594, 10.1002/(SICI)1097-4547(20000601)60:5<594::AID-JNR4>3.0.CO;2-6 Demeule, 2001, Isolation of endothelial cells from brain, lung, and kidney: expression of the multidrug resistance P-glycoprotein isoforms, Biochem. Biophys. Res. Commun., 281, 827, 10.1006/bbrc.2001.4312 El Hafny, 1997, Modulation of P-glycoprotein activity by glial factors and retinoic acid in an immortalized rat brain microvessel endothelial cell line, Neurosci. Lett., 236, 107, 10.1016/S0304-3940(97)00679-4 Yang, 2001, Transendothelial permeability of chlorpyrifos in RBE4 monolayers is modulated by astrocyte-conditioned medium, Brain Res. Mol. Brain. Res., 97, 43, 10.1016/S0169-328X(01)00296-0 Sobue, 1999, Induction of blood–brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors, Neurosci. Res., 35, 155, 10.1016/S0168-0102(99)00079-6 Gaillard, 2001, Establishment and functional characterization of an in vitro model of the blood–brain barrier, comprising a co-culture of brain capillary endothelial cells and astrocytes, Eur. J. Pharm. Sci., 12, 215, 10.1016/S0928-0987(00)00123-8 Hayashi, 1997, Induction of various blood–brain barrier properties in non-neural endothelial cells by close apposition to co-cultured astrocytes, Glia, 19, 13, 10.1002/(SICI)1098-1136(199701)19:1<13::AID-GLIA2>3.0.CO;2-B Rao, 1999, 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. USA, 96, 3900, 10.1073/pnas.96.7.3900 Warren, 2000, Effect of P-glycoprotein modulation with cyclosporin A on cerebrospinal fluid penetration of doxorubicin in nonhuman primates, Cancer Chemother. Pharmacol., 45, 207, 10.1007/s002800050031 Gumbleton, 2001, Progress and limitations in the use of in vitro cell cultures to serve as permeability screen for the blood–brain barrier, J. Pharm. Sci., 90, 1681, 10.1002/jps.1119 Audus, 1987, Bovine brain microvessel endothelial cell monolayers as a model system for the blood–brain barrier, Ann. NY Acad. Sci., 507, 9, 10.1111/j.1749-6632.1987.tb45787.x Johnson, 1999, In vitro models of the blood–brain barrier to polar permeants: Comparison of transmonolayer flux measurements and cell uptake kinetics using cultured cerebral capillary endothelial cells, J. Pharm. Sci., 88, 620, 10.1021/js9803149 Miller, 1992, Application of cultured endothelial cells of the brain microvasculature in the study of the blood–brain barrier, J. Tiss. Cult. Meth., 14, 217, 10.1007/BF01409014 Ichikawa, 1996, Isolation and primary culture of rat cerebral microvascular endothelial cells for studying drug transport in vitro, J. Pharmacol. Toxicol. Methods, 36, 45, 10.1016/1056-8719(96)00072-X Galla, 2000, Primary cultures of brain microvessel endothelial cells: a valid and flexible model to study drug transport through the blood–brain barrier in vitro, Brain Res. Prot., 5, 248, 10.1016/S1385-299X(00)00020-9 Ghazanfari, 2001, Characteristics of endothelial cells derived from the blood–brain barrier and of astrocytes in culture, Brain Res., 890, 49, 10.1016/S0006-8993(00)03053-5 Begley, 1996, Functional expression of P-glycoprotein in an immortalised cell line of rat brain endothelial cells, RBE4, J. Neurochem., 67, 988, 10.1046/j.1471-4159.1996.67030988.x Regina, 1999, Dexamethasone regulation of P-glycoprotein activity in an immortalized rat brain endothelial cell line, GPNT, J. Neurochem., 73, 1954, 10.1046/j.1471-4159.1999.01954.x Terasaki, 2001, Conditionally immortalized cell lines as a new in vitro model for the study of barrier functions, Biol. Pharm. Bull., 24, 111, 10.1248/bpb.24.111 Pardridge, 1990, Comparison of in vitro and in vivo models of drug transcytosis through the blood–brain barrier, J. Pharmacol. Exp. Ther., 253, 884 Hansen, 2002, Comparison of in vitro BBMEC permeability and in vivo CNS uptake by microdialysis sampling, J. Pharm. Biomed. Anal., 27, 945, 10.1016/S0731-7085(01)00542-8 Glynn, 1998, In vitro blood–brain barrier permaeability of nevirapine compared to other HIV antiretroviral agents, J. Pharm. Sci., 87, 306, 10.1021/js970291i van der Sandt, 2001, Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood–brain barrier, AIDS, 15, 483, 10.1097/00002030-200103090-00007 Elmquist, 2001, The use of transgenic animals for pharmacokinetics and pharmacodynamics studies, J. Pharm. Sci., 90, 422, 10.1002/1520-6017(200104)90:4<422::AID-JPS1001>3.0.CO;2-Z Schinkel, 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, 10.1016/0092-8674(94)90212-7 Schinkel, 1995, Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A, J. Clin. Invest., 96, 1698, 10.1172/JCI118214 Schinkel, 1996, P-glycoproetin in the blood–brain barrier of mice influences the brain penetration and pharmacological activity of many drugs, J. Clin. Invest., 97, 2517, 10.1172/JCI118699 van Asperen, 1996, Altered pharmacokinetics of vinblastine in Mdr1a-P-glycoprotein-deficient Mice, J. Nat. Cancer Inst., 88, 994, 10.1093/jnci/88.14.994 van Asperen, 1999, Comparative pharmacokinetics of vinblastine after a 96-h continuous infusion in wild-type mice and mice lacking mdr1a P-glycoprotein, J. Pharmacol. Exp. Ther., 289, 329 Schinkel, 1997, Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins, Proc. Natl. Acad. Sci., 94, 4028, 10.1073/pnas.94.8.4028 Kawahara, 1999, Physiologically based pharmacokinetics of digoxin in mdr1a knockout mice, J. Pharm. Sci., 88, 1281, 10.1021/js9901763 Kim, 1998, The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors, J. Clin. Invest., 101, 289, 10.1172/JCI1269 Polli, 1999, Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor, Pharm. Res., 16, 1206, 10.1023/A:1018941328702 Huisman, 2001, P-glycoprotein limits oral availability, brain and fetal penetration of saquinavir even with high doses of ritonavir, Mol. Pharmacol., 59, 806, 10.1124/mol.59.4.806 Jonkers, 1999, 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., 127, 43, 10.1038/sj.bjp.0702497 Yokogawa, 1999, P-glycoprotein-dependent disposition kinetics of tacrolimus: studies in mdr1a knockout mice, Pharm. Res., 16, 1213, 10.1023/A:1018993312773 Xie, 1999, The role of P-glycoprotein in blood–brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (−/−) and mdr1a (+/+) mice, Br. J. Pharmacol., 128, 563, 10.1038/sj.bjp.0702804 Dagenais, 2001, Effect of mdr1a P-glycoprotein gene disruption, gender, and substrate concentration on brain uptake of selected compounds, Pharm. Res., 18, 957, 10.1023/A:1010984110732 Cisternino, 2001, Screening of multidrug-resistance sensitive drugs by in situ brain perfusion in P-glycoprotein-deficient mice, Pharm. Res., 18, 183, 10.1023/A:1011080418027 Uhr, 2000, 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, 380, 10.1016/S0893-133X(99)00095-0 de Lange, 2000, In vitro and in vivo investigations on fluoroquinolones; effects of the P-glycoprotein efflux transporter on brain distribution of sparfloxacin, Eur. J. Pharm. Sci., 12, 85, 10.1016/S0928-0987(00)00149-4 Lankas, 1997, P-glycoprotein deficiency in a subpopulation of CF-1 mice enhances avermectin-induced neurotoxicity, Toxicol. Appl. Pharmacol., 143, 357, 10.1006/taap.1996.8086 Umbenhaurer, 1997, Identification of a P-glycoprotein-deficient subpopulation in the CF-1 mouse strain using a restriction fragment length polymorphism, Toxicol. Appl. Pharmacol., 146, 88, 10.1006/taap.1997.8225 Kwei, 1999, Disposition of ivermectin and cyclosporin A in CF-1 mice deficient in mdr1a P-glycoprotein, Drug Metab. Dispos., 27, 581 Dagenais, 2000, Development of an in situ mouse brain perfusion model and its application to mdr1a P-glycoprotein-deficient mice, J. Cereb. Blood Flow Metab., 20, 381, 10.1097/00004647-200002000-00020 Liu, 2002, Multidrug-resistance mdr1a/1b double knockout mice are more sensitive than wild type mice to acute arsenic toxicity, with higher arsenic accumulation in tissues, Toxicology, 170, 55, 10.1016/S0300-483X(01)00532-7 Yamazaki, 2001, In vitro substrate identification studies for P-glycoprotein-mediated transport: species difference and predicatability of in vivo results, J. Pharmacol. Exp. Ther., 296, 723 Adachi, 2001, Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein, Pharm. Res., 18, 1660, 10.1023/A:1013358126640 Smith, 2001, P-glycoprotein efflux at the blood–brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related beurokinin-1 receptor antagonists, J. Pharmacol. Exp. Ther., 298, 1252 Sawchuk, 2000, Microdialysis in the study of drug transporters in the CNS, Adv. Drug Deliv. Rev., 45, 295, 10.1016/S0169-409X(00)00104-6 Wang, 1995, Effect of the p-glycoprotein inhibitor, cyclosporin A, on the distribution of rhodamine-123 to the brain: an in vivo microdialysis study in freely moving rats, Biochem. Biophys. Res. Commun., 211, 719, 10.1006/bbrc.1995.1872 de Lange, 1998, BBB transport and P-glycoprotein functionality using MDR1A (−/−) and wild-type mice. Total brain versus microdialysis concentration profiles of rhodamine-123, Pharm. Res., 15, 1657, 10.1023/A:1011988024295 Tsai, 2001, Pharmacokinetics of pefloxacin and its interaction with cyclosporin A, a P-glycoprotein modulator, in rat blood, brain and bile, using simultaneous microdialysis, Br. J. Pharmacol., 132, 1310, 10.1038/sj.bjp.0703927 Chang, 2001, Effect of cyclosporin, a P-glycoprotein inhibitor, on the pharmacokinetics of cefepime in rat blood and brain: a microdialysis study, Life. Sci., 69, 191, 10.1016/S0024-3205(01)01103-1 Tsai, 2001, Effect of P-glycoprotein modulators on the pharmacokinetics of camptothecin using microdialysis, Br. J. Pharmacol., 134, 1245, 10.1038/sj.bjp.0704363 Dan, 2002, Distribution of domperidone into the rat brain is increased by brain ischaemia or treatment with the P-glycoprotein inhibitor verapamil, J. Pharm. Pharmacol., 54, 729, 10.1211/0022357021778880 Potschka, 2001, 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, 3557, 10.1097/00001756-200111160-00037 Potschka, 2001, In vivo evidence for P-glycoprotein-mediated transport of phenytoin at the blood–brain barrier of rats, Epilepsia, 42, 1231, 10.1046/j.1528-1157.2001.01901.x N.H. Handrikse, W. Vaalburg, Imaging of P-glycoprotein function in vivo with PET, Novartis Found. Symp., 243(2002) 137–45, 145–8, 180–5. N.H. Handrikse, J. Bart, E.G. de Vries, H.J. Groen, W.T. van der Graaf, W. Vaalburg, P-glycoprotein at the blood–brain barrier and analysis of drug transport with positron-emission tomography, J. Clin. Pharmacol., Suppl. (2001) 48S–54S. Doze, 2000, Enhanced cerebral uptake of receptor ligands by modulation of P-glycoprotein function in the blood–brain barrier, Synapse, 36, 66, 10.1002/(SICI)1098-2396(200004)36:1<66::AID-SYN7>3.0.CO;2-J Handrikse, 1999, A new in vivo method to study P-glycoprotein transport in tumors and the blood–brain barrier, Cancer Resm., 59, 2411 Handrikse, 1998, Complete in vivo reversal of P-glycoprotein pump function in the blood–brain barrier visualized with positron emission tomography, Br. J. Pharmacol., 124, 1413, 10.1038/sj.bjp.0701979 Passchier, 2000, Influence of P-glycoprotein on brain uptake of [18F]MPPF in rats, Eur. J. Pharmacol., 407, 273, 10.1016/S0014-2999(00)00752-4 Luker, 1997, Characterization of phosphine complexes of technetium(III) as transport substrates of the multidrug resistance P-glycoprotein and functional markers of P-glycoprotein at the blood-brain barrier, Biochemistry, 36, 14218, 10.1021/bi971931z Chen, 2000, Effects of MDR1 and MDR3 P-glycoprotein, MRP1, and BCRP/MXR/ABCP on the transport of (99m) Tc-tetrofosmin, Biochem. Pharmacol., 60, 413, 10.1016/S0006-2952(00)00341-5 Cole, 1992, Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line, Science, 258, 1650, 10.1126/science.1360704 Flens, 1996, Am. J. Pathol., 148, 1237 Buchler, 1996, cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats, J. Biol. Chem., 271, 15091, 10.1074/jbc.271.25.15091 Taniguchi, 1996, A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation, Cancer Res., 56, 4124 Kool, 1997, Analysis of expression of cMOAT (MRP2), MRP2, MRP4, and MRP5, Homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines, Cancer Res., 57, 3537 Kool, 1999, Expression of MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells, Cancer Res., 59, 175 Hopper, 2001, Analysis of the structure and expression pattern of MRP7 (ABCC10), a new member of the MRP subfamily, Cancer Lett., 162, 181, 10.1016/S0304-3835(00)00646-7 Kao, 2002, cDNA cloning and genomic organization of the murine MRP7, a new ATP-binding cassette transporter, Gene, 286, 299, 10.1016/S0378-1119(02)00461-4 Bera, 2001, MRP8, a new member of the ABC transporter superfamily, identified by EST database mining and gene prediction program, is highly expressed in breast cancer, Mol. Med., 7, 509, 10.1007/BF03401856 Bera, 2002, MRP9, an unusual truncated member of the ABC transporter superfamily, is highly expressed in breast cancer, Proc. Natl. Acad. Sci., 99, 6997, 10.1073/pnas.102187299 Kusuhara, 1998, Characterization of efflux transport of organic anions in a mouse brain capillary endothelial cell line, J. Pharmacol. Exp. Ther., 285, 1260 Homma, 1999, High-affinity efflux transport system for glutathione conjugate on the luminal membrane of a mouse brain capillary endothelial cell line (MBEC4), J. Pharmacol. Exp. Ther., 288, 198 Ghersi-Egea, 1994, Localization of drug-metabolizing enzyme activities to blood–brain interfaces and circumventricular organs, J. Neurochem., 62, 1089, 10.1046/j.1471-4159.1994.62031089.x Huai-Yun, 1998, Expression of multidrug resistance protein (MRP) in brain microvessel endothelial cells, Biochem. Biophys. Res. Commun., 243, 816, 10.1006/bbrc.1997.8132 Zhang, 2000, Expression of multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells, Brain. Res., 876, 148, 10.1016/S0006-8993(00)02628-7 Sun, 2001, Transport of fluorescein in MDCKII-MRP1 transfected cells and mrp1-knockout mice, Biochem. Biophys. Res. Commun., 284, 863, 10.1006/bbrc.2001.5062 Sun, 2001, Effect of probenecid on fluorescein transport in the central nervous system using in vitro and in vivo models, Pharm. Res., 18, 1542, 10.1023/A:1013074229576 Seetharaman, 1998, Multidrug resistance-related transport proteins in isolated human brain microvessels and in cells cultured from these isolates, J. Neurochem., 70, 1151, 10.1046/j.1471-4159.1998.70031151.x Gutmann, 1999, Modulation of multidrug resistance protein expression in porcine brain capillary endothelial cells in vitro, Drug. Metab. Dispos., 27, 937 Regina, 1998, Mrp1 Multidrug resistance-associated protein and P-glycoprotein expression in rat brain microvessel endothelial cells, J. Neurochem., 71, 705, 10.1046/j.1471-4159.1998.71020705.x Wijnholds, 2000, Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood–cerebrospinal fluid barrier, J. Clin. Invest., 105, 279, 10.1172/JCI8267 Seetharaman, 1998, Changes in multidrug transporter protein expression in endothelial cells cultured from isolated human brain microvessels, Int. J. Clin. Pharmacol. Ther., 36, 81 McAleer, 1999, pABC11 (Also known as MOAT-C and MRP5). A member of the ABC family of proteins, has anion transporter activity but dose not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells, J. Biol. Chem., 274, 23541, 10.1074/jbc.274.33.23541 Wijnholds, 2000, Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs, Proc. Natl. Acad. Sci. USA, 97, 7476, 10.1073/pnas.120159197 Jedlitschky, 2000, The multidrug resistance protein 5(MRP5) functions as an ATP-dependent export pump for cyclic nucleotides, J. Biol. Chem., 275, 30069, 10.1074/jbc.M005463200 Sweet, 2002, Impaired organic anion transport in kidney and choroids plexus of organic anion transporter 3 (Oat3(Slc22a8)) knockout mice, J. Biol. Chem., 277, 26934, 10.1074/jbc.M203803200 Takasawa, 1997, In vivo evidence for carrier-mediated efflux of 3′-azido-3′-deoxythymidine and 2′, 3′-dideoxyinosine across the blood–brain barrier via a probenecid-sensitive transport system, J. Pharmacol. Exp. Ther., 281, 369 Kitazawa, 1998, Efflux of taurocholic acid across the blood–brain barrier: interaction with cyclic peptides, J. Pharmacol. Exp. Ther., 286, 890 Wada, 2000, Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs, J. Pharmacol. Exp. Ther., 294, 844 Kusuhara, 1999, Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain, J. Biol. Chem., 274, 13675, 10.1074/jbc.274.19.13675 Sekine, 2000, The multispecific organic anion transporter (OAT) family, Pflugers. Arch—Eur. J. Physiol., 440, 337, 10.1007/s004240000297 Sekine, 1997, Expression cloning and characterization of a novel multispecific organic anion transporter, J. Biol. Chem., 272, 18526, 10.1074/jbc.272.30.18526 Asaba, 2000, Blood–brain barrier is involved in the efflux transport of a neuroactive steroid, dehydroepiandrosterone sulfate, via organic anion transporting polypeptide 2, J. Neurochem., 75, 1907, 10.1046/j.1471-4159.2000.0751907.x Gerhart, 1997, Expression of monocarboxylate transporter MCT1 by brain endothelium and glia in adult and suckling rats, Am. J. Physiol., 273, E207 Kido, 2000, Functional clarification of MCT1-mediated transport of monocarboxylic acids at the blood–brain barrier using in vitro cultured cells and in vivo BUI studies, Pharm. Res., 17, 55, 10.1023/A:1007518525161 Leier, 1994, The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates, J. Biol. Chem., 269, 27807, 10.1016/S0021-9258(18)46856-1 Evers, 1998, Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA, J. Clin. Invest., 101, 1310, 10.1172/JCI119886 Jedlitschky, 1996, Transport of glutathione, glucuronate, and sulfate conjugates by the MRP gene-encoded conjugate export pump, Cancer Res., 56, 988 Loe, 1996, Multidrug resistance protein (MRP)-mediated transport of leukotriene C4 and chemotherapeutic agents in membrane vesicles. Demonstration of glutathione-dependent vincristine transport, J. Biol. Chem., 271, 9675, 10.1074/jbc.271.16.9675 Leier, 1996, ATP-dependent glutathione disulphide transport mediated by the MRP gene-encoded conjugate export pump, Biochem. J., 314, 433, 10.1042/bj3140433 Loe, 1997, ATP-dependent transport of aflatoxin B1 and its glutathione conjugates by the product of the multidrug resistance protein (MRP) gene, Mol. Pharmacol., 51, 1034, 10.1124/mol.51.6.1034 Zaman, 1996, Transport of the glutathione conjugate of ethacrynic acid by the human multidrug resistance protein MRP, FEBS Lett., 391, 126, 10.1016/0014-5793(96)00718-1 Evers, 1997, Transport of glutathione prostaglandin A conjugates by the multidrug resistance protein 1, FEBS Lett., 419, 112, 10.1016/S0014-5793(97)01442-7 Loe, 1998, Characterization of vincrinstine transport by the Mr 190 000 multidrug resistance protein (MRP): evidence for cotransport with reduced glutathione, Cancer Res., 58, 5130 Renes, 1999, ATP- and glutathione-dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1, Br. J. Pharmacol., 126, 681, 10.1038/sj.bjp.0702360 Keppler, 1999, Export pumps for anionic conjugates encoded by MRP genes, Adv. Enz. Regul., 39, 237, 10.1016/S0065-2571(98)00015-6 Hooijberg, 1999, Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2, Cancer Res., 59, 2532 Schuetz, 1999, MRP4: a previously unidentified factor in resistance to nucleoside-based antiviral drugs, Nature Med., 5, 1048, 10.1038/12487 Madon, 2000, Transport function and hepatocellular localization of mrp6 in rat liver, Mol. Pharmacol., 57, 634, 10.1124/mol.57.3.634 Jacquemin, 1994, Expression cloning of a rat liver Na+-independent organic anion transporter, Proc. Natl. Acad. Sci. USA, 91, 133, 10.1073/pnas.91.1.133 Li, 1998, Identification of glutathione as a driving force and leukotriene C-4 as a substrate for Oatp1, the hepatic sinusoidal organic solute transporter, J Biol. Chem., 273, 16184, 10.1074/jbc.273.26.16184 Eckhardt, 1999, Polyspecific substrate uptake by the hepatic organic anion transporter Oatp1 in stably transfected CHO cells, Am. J. Physiol., 276, G1037 Bossuyt, 1996, Polyspecific drug and steroid clearance by an organic anion transporter of mammalian liver, J. Pharmacol. Exp. Ther., 276, 891 van Aubel, 2000, Molecular pharmacology of renal organic anion transporters, Am. J. Physiol. Renal Physiol., 279, F216, 10.1152/ajprenal.2000.279.2.F216 van Montfoort, 1999, Polyspecific organic anion transporting polypeptides mediate hepatic uptake of amphipathic type II organic cations, J. Pharmacol. Exp. Ther., 291, 147 Eckhardt, 1996, The peptide-based thrombin inhibitor CRC 220 is a new substrate of the basolateral rat liver organic anion-transporting polypeptide, Hepatology, 24, 380, 10.1002/hep.510240215 Pang, 1998, The modified dipeptide, enalapril, an angiotensin-converting enzyme inhibitor, is transported by the rat liver organic anion transport protein, Hepatology, 28, 1341, 10.1002/hep.510280524 Ishizuka, 1998, Transport of temocaprilat into rat hepatocytes: role of organic anion transporting polypeptide, J. Pharmacol. Exp. Ther., 287, 37 Gao, 2000, Organic anion-transporting polypeptides mediate transport of opioid peptides across blood–brain barrier, J. Pharmacol. Exp. Ther., 294, 73 Kontaxi, 1996, Uptake of the mycotoxin ochratoxin A in liver cells occurs via the cloned organic anion transporting polypeptide, J. Pharmacol. Exp. Ther., 279, 1507 Reichel, 1999, Localization and function of the organic anion-transporting polypeptide Oatp2 in rat liver, Gastroenterology, 117, 688, 10.1016/S0016-5085(99)70463-4 Friesema, 1999, Identification of thyroid hormone transporters, Biochem. Biophys. Res. Commun., 254, 497, 10.1006/bbrc.1998.9974 Noe, 1997, Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain, Proc. Natl. Acad. Sci. USA, 94, 10346, 10.1073/pnas.94.19.10346 Abe, 1998, Molecular characterization and tissue distribution of a new organic transporter subtype (oatp3) that transports thyroid hormones and taurocholate and comparison with oatp2, J. Biol. Chem., 273, 22395, 10.1074/jbc.273.35.22395 Kullak-Ublick, 1995, Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver, Gastroenterology, 109, 1274, 10.1016/0016-5085(95)90588-X Bossuyt, 1996, Multispecific amphipathic substrate transport by an organic anion transporter of human liver, J. Hepatol., 25, 733, 10.1016/S0168-8278(96)80246-7 Kullak-Ublick, 1999, Regulation of organic anion and drug transporters of the sinusoidal membrane, J. Hepatol., 31, 563, 10.1016/S0168-8278(99)80054-3 Uwai, 1998, Functional characterization of the rat multispecific organic anion transporter OAT1 mediating basolateral uptake of anionic drugs in the kidney, FEBS. Lett., 438, 321, 10.1016/S0014-5793(98)01328-3 Apiwattanakul, 1999, Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes, Mol. Pharmacol., 55, 847 Tsuda, 1999, Transport of ochratoxin A by renal multispecific organic anion transporter 1, J. Pharmacol. Exp. Ther., 289, 1301 Jariyawat, 1999, The interaction and transport of β-lactam antibiotics with the cloned rat renal organic an transporter 1, J. Pharmacol. Exp. Ther., 290, 672 Kakee, 1997, Selective brain to blood efflux transport of p-aminohippuric acid across the blood–brain barrier: in vivo evidence by use of the brain efflux index method, J. Pharmacol. Exp. Ther., 283, 1018 Banks, 1990, Permeability of the murine blood–brain barrier to some octapeptide analogs of somatostatin, Proc. Natl. Acad. Sci. USA, 87, 6762, 10.1073/pnas.87.17.6762 Banks, 1994, Saturable efflux of the peptides RC-160 and Tyr-MIF-1 by different parts of the blood–brain barrier, Brain Res. Bull., 35, 179, 10.1016/0361-9230(94)90100-7 Leininger, 1991, In vivo study of the elimination from rat brain of an intracerebrally formed xenobiotic metabolite, 1-naphthyl-β-d-glucuronide, J. Neurochem., 56, 1163, 10.1111/j.1471-4159.1991.tb11406.x Cornford, 1985, Blood–brain barrier transport of valproic acid, J. Neurochem., 44, 1541, 10.1111/j.1471-4159.1985.tb08793.x Adkison, 1994, Contribution of probenecid-sensitive anion transport processes at the brain capillary endothelium and choroid plexus to the efficient efflux of valproic acid from the central nervous system, J. Pharmacol. Exp. Ther., 268, 797 Adkison, 1996, Effect of p-aminohippurate on the efflux of valproic acid from the central nervous system of the rabbit, Epilepsy Res., 23, 95, 10.1016/0920-1211(95)00092-5 Scism, 1997, Effects of probenecid on brain–cerebrospinal fluid–blood distribution kinetics of E-Delta 2-valproic acid in rabbits, Drug Metab. Dispos., 25, 1337 Emanuelsson, 1987, Probenecid-induced accumulation of 5-hydroxyindoleacetic acid and homovanillic acid in rat brain, J. Pharm. Pharmacol., 39, 705, 10.1111/j.2042-7158.1987.tb06973.x Morrison, 1999, Quinolinic acid is extruded from the brain by a probenecid-sensitive carrier system: a quantitative analysis, J. Neurochem., 72, 2135, 10.1046/j.1471-4159.1999.0722135.x Deguchi, 2000, Brain distribution of 6-mercaptopurine is regulated by the efflux transport system in the blood–brain barrier, Life. Sci., 66, 649, 10.1016/S0024-3205(99)00637-2 Deguchi, 1995, Study on brain interstitial fluid distribution and blood–brain barrier transport of baclofen in rats by microdialysis, Pharm. Res., 12, 1838, 10.1023/A:1016263032765 Bergeron, 1995, Effect of probenecid on 5-hydroxyindoleacetic acid in cisternal cerebrospinal fluid of rats with portacaval anastomosis, Neurochem. Res., 20, 963, 10.1007/BF00970743 Kim, 1987, Effect of 2,4,5-trichlorophenoxyacetic acid and quinolinic acid on 5-hydroxy-3-indoleacetic acid transport by the rabbit choroid plexus: pharmacology and electron microscopic cytochemistry, Toxicol. Appl. Pharmacol., 90, 436, 10.1016/0041-008X(87)90136-0 Kim, 1992, Octanoic acid produces accumulation of monoamine acidic metabolites in the brain: interaction with organic anion transport at the choroid plexus, J. Neurochem., 58, 1499, 10.1111/j.1471-4159.1992.tb11370.x Spector, 1976, Inhibition of methotrexate transport from cerebrospinal fluid by probenecid, Cancer Treat Rep., 60, 913 Dixon, 1969, Evidence of active transport of benzyl-14C-penicillin from cerebrospinal fluid to blood, J. Pharm. Sci., 58, 1106, 10.1002/jps.2600580914 Ogawa, 1994, Kinetics of active efflux via choroid plexus of β-lactam antibiotics from the CSF into the circulation, Am. J. Physiol., 266, R392 Ooie, 1996, Characterization of the transport properties of quinolone antibiotic, fleroxacin, in rat choroid plexus, Pharm. Res., 13, 523, 10.1023/A:1016081618149 Nohjoh, 1989, Transport of cefodizime, a novel third generation cephalosporin antibiotic, in isolated rat choroid plexus, J. Pharmacol. Exp. Ther., 250, 324 Kim, 1993, Transport of 2,4,5-trichlorophenoxyacetic acid across the blood–cerebrospinal fluid barrier of the rabbit, J. Pharmacol. Exp. Ther., 267, 751 Pritchard, 1980, Accumulation of anionic pesticides by rabbit choroid plexus in vitro, J. Pharmacol. Exp. Ther., 212, 54 Nishino, 1999, Transepithelial transport of organic anions across the choroid plexus: possible involvement of organic anion transporter and multidrug resistance-associated protein, J. Pharmacol. Exp. Ther., 290, 289 Takasawa, 1997, Transport properties of 3′-azido-3′-deoxythymidine and 2′, 3′-dideoxyinosine in the rat choroid plexus, Biopharm. Drug Disposition., 18, 611, 10.1002/(SICI)1099-081X(199710)18:7<611::AID-BDD45>3.0.CO;2-2 Masereeuw, 1994, In vitro and in vivo transport of zidovudine (AZT) across the blood–brain barrier and the effect of transport inhibitors, Pharm. Res., 11, 324, 10.1023/A:1018932213953 Wang, 1997, Zidovudine transport within the rabbit brain during intracerebroventricular administration and the effect of probenecid, J. Pharm. Sci., 86, 1484, 10.1021/js950330v Kitazawa, 2000, In vivo and in vitro evidence of a carrier-mediated efflux transport system for oestrone-3-sulphate across the blood–cerebrospinal fluid barrier, J. Pharm. Pharmacol., 52, 281, 10.1211/0022357001773968 Spector, 1985, Leukotriene C4 transport by the choroid plexus in vitro, Science, 228, 325, 10.1126/science.3983632 Spector, 1986, Pantothenic acid transport and metabolism in the central nervous system, Am. J. Physiol., 250, R292 Suzuki, 1986, Transport of cimetidine by the rat choroid plexus in vitro, J. Pharmacol. Exp. Ther., 239, 927 Naora, 1996, Saturable transport of valproic acid in rat choroid plexus in vitro, J. Pharm. Sci., 85, 423, 10.1021/js950436q Kanai, 1996, Estrdiol 17β-d-glucuronide is a high-affinity substrate for oatp organic anion transporter, Am. J. Physiol., 270, F326 Kanai, 1995, Identification and characterization of a prostaglandin transporter, Science (Wash. DC), 268, 866, 10.1126/science.7754369 Gao, 1999, Localization of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroid plexus epithelium of rat brain, J. Histochem. Cytochem., 47, 1255, 10.1177/002215549904701005 Walters, 2000, Expression, transport properties, and chromosomal location of organic anion transporter subtype 3, Am. J. Physiol. Gastroinest. Liver Physiol., 279, 1188, 10.1152/ajpgi.2000.279.6.G1188 Y. Zhang, J.D. Schuetz, W.F. Elmquist, D.W. Milller, Plasma membrane localization of multidrug resistance-associated protein (MRP) homologues in brain capillary endothelial cells, J. Neurochem., submitted for publication. Sugiyama, 2001, Characterization of efflux transport of 17 β-estradiol-d-glucuronide from the brain across the blood–brain barrier, J. Pharmacol. Exp. Ther., 298, 316 Gibbs, 2002, The distribution of the anti-HIV drug, 2′3′-dideoxycytidine(ddC), across the blood–brain barrier and blood–cerebrospinal fluid barriers and the influence of organic anion transport inhibitors, J. Neurochem., 80, 392, 10.1046/j.0022-3042.2001.00711.x Miller, 2000, Xenobiotic transport across isolated brain microvessels studied by confocal microscopy, Mol. Pharmacol., 58, 1357, 10.1124/mol.58.6.1357 Pritchard, 1999, Mechanism of organic anion transport across the apical membrane of choroid plexus, J. Biol. Chem., 274, 33382, 10.1074/jbc.274.47.33382 Angeletti, 1997, The choroid plexus epithelium is the site of the organic anion transport protein in the brain, Proc. Natl. Acad. Sci. USA, 94, 283, 10.1073/pnas.94.1.283