The role of drug transporters at the blood-brain barrier.

The blood-brain barrier (BBB) is a dynamic interface between the blood and the brain. It eliminates (toxic) substances from the endothelial compartment and supplies the brain with nutrients and other (endogenous) compounds. It can be considered as an organ protecting the brain and regulating its homeostasis. Until now, many transport systems have been discovered that play an important role in maintaining BBB integrity and brain homeostasis. In this review, we focus on the role of carrier- and receptor-mediated transport systems (CMT, RMT) at the BBB. These include CMT systems, such as P-glycoprotein, multidrug-resistance proteins 1-7, nucleoside transporters, organic anion transporters, and large amino-acid transporters; RMT systems, such as the transferrin-1 and -2 receptors; and the scavenger receptors SB-AI and SB-BI.

[1]  J. Hofmann.  Modulation of protein kinase C in antitumor treatment. , 2001, Reviews of physiology, biochemistry and pharmacology.

[2]  M Gumbleton,et al.  Progress and limitations in the use of in vitro cell cultures to serve as a permeability screen for the blood-brain barrier. , 2001, Journal of pharmaceutical sciences.

[3]  W. Pardridge.  Blood-brain barrier transport of nutrients. , 2009, Nutrition reviews.

[4]  M. Tardieu.  HIV-1-related central nervous system diseases. , 1999, Current opinion in neurology.

[5]  D. Breimer,et al.  P-Glycoprotein Inhibition Leads to Enhanced Disruptive Effects by Anti-Microtubule Cytostatics at the In Vitro Blood-Brain Barrier , 2001, Pharmaceutical Research.

[6]  G. Siest,et al.  Drug metabolizing enzymes in the brain and cerebral microvessels , 1991, Brain Research Reviews.

[7]  R. Fine,et al.  Phorbol esters induce multidrug resistance in human breast cancer cells. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[8]  C. Lok,et al.  The transferrin receptor: role in health and disease. , 1999, The international journal of biochemistry & cell biology.

[9]  M. Kool,et al.  A family of drug transporters: the multidrug resistance-associated proteins. , 2000, Journal of the National Cancer Institute.

[10]  H. Yawo,et al.  Immunohistochemical distribution and functional characterization of an organic anion transporting polypeptide 2 (oatp2) , 1999, FEBS letters.

[11]  M. C. Ellis,et al.  A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis , 1996, Nature Genetics.

[12]  C. Ringbom,et al.  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. , 2001, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[13]  W. Pardridge,et al.  Selective expression of the large neutral amino acid transporter at the blood-brain barrier. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[14]  H. M. Bender,et al.  Role of blood‐brain barrier P‐glycoprotein in limiting brain accumulation and sedative side‐effects of asimadoline, a peripherally acting analgaesic drug , 1999, British journal of pharmacology.

[15]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[16]  C. Cass,et al.  Distribution of mRNA encoding a nitrobenzylthioinosine-insensitive nucleoside transporter (ENT2) in rat brain. , 1999, Brain research. Molecular brain research.

[17]  P. Borst,et al.  Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. , 1995, The Journal of clinical investigation.

[18]  A. Moses,et al.  HIV infection of human brain capillary endothelial cells--implications for AIDS dementia. , 1994, Advances in neuroimmunology.

[19]  F. Field,et al.  Esterification of plasma membrane cholesterol and triacylglycerol-rich lipoprotein secretion in CaCo-2 cells: possible role of p-glycoprotein. , 1995, Journal of lipid research.

[20]  Thomas J. Raub,et al.  Recycling kinetics and transcytosis of transferrin in primary cultures of bovine brain microvessel endothelial cells , 1991, Journal of cellular physiology.

[21]  R. Rhodes.  Evidence of Serum-Protein Leakage Across the Blood-Brain Barrier in the Acquired Immunodeficiency Syndrome , 1991, Journal of neuropathology and experimental neurology.

[22]  R. G. Anderson.  The caveolae membrane system. , 1998, Annual review of biochemistry.

[23]  K R Scott,et al.  Influence of multidrug resistance (MDR) proteins at the blood-brain barrier on the transport and brain distribution of enaminone anticonvulsants. , 2001, Journal of pharmaceutical sciences.

[24]  M. Yazdanian,et al.  In vitro blood-brain barrier permeability of nevirapine compared to other HIV antiretroviral agents. , 1998, Journal of pharmaceutical sciences.

[25]  W N Kelley,et al.  The role of adenosine and 2'-deoxyadenosine in mammalian cells. , 1978, Annual review of biochemistry.

[26]  M C Willingham,et al.  Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[27]  A. Schinkel,et al.  P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. , 1996, The Journal of clinical investigation.

[28]  A. Munn.  Molecular requirements for the internalisation step of endocytosis: insights from yeast. , 2001, Biochimica et biophysica acta.

[29]  W. Jefferies,et al.  Reactive microglia specifically associated with amyloid plaques in Alzheimer's disease brain tissue express melanotransferrin , 1996, Brain Research.

[30]  M. Hashida,et al.  Uptake and gene expression of naked plasmid DNA in cultured brain microvessel endothelial cells. , 1998, Biochemical and biophysical research communications.

[31]  D. R. van der Westhuyzen,et al.  Scavenger receptor class B, type I is expressed in porcine brain capillary endothelial cells and contributes to selective uptake of HDL‐associated vitamin E , 2001, Journal of neurochemistry.

[32]  W. Wilson,et al.  Melphalan penetration of the blood-brain barrier via the neutral amino acid transporter in tumor-bearing brain. , 1992, Cancer research.

[33]  M. Gumbleton.  Caveolae-mediated membrane transport. , 2001, Advanced drug delivery reviews.

[34]  J. Tainer,et al.  Transferrin receptor internalization sequence YXRF implicates a tight turn as the structural recognition motif for endocytosis , 1990, Cell.

[35]  J. Kuiper,et al.  Characterization of the Scavenger Receptor on Bovine Cerebral Endothelial Cells In Vitro , 1993, Journal of neurochemistry.

[36]  Peter B. Reiner,et al.  β‐Amyloid efflux mediated by p‐glycoprotein , 2001 .

[37]  J. Williams,et al.  Primary structure of human transferrin receptor deduced from the mRNA sequence , 1984, Nature.

[38]  K. Brouwer,et al.  Effects of a potent and specific P-glycoprotein inhibitor on the blood-brain barrier distribution and antinociceptive effect of morphine in the rat. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[39]  M. Gottesman,et al.  Is the multidrug transporter a flippase? , 1992, Trends in biochemical sciences.

[40]  A. Nehlig,et al.  Physiological and pharmacological properties of adenosine: therapeutic implications. , 1991, Life sciences.

[41]  M. Segal,et al.  Saturation kinetics, specificity and NBMPR sensitivity of thymidine entry into the central nervous system , 1997, Brain Research.

[42]  J. Couet,et al.  Cell biology of caveolae and caveolin. , 2001, Advanced drug delivery reviews.

[43]  A. Tall,et al.  High Density Lipoprotein (HDL) Particle Uptake Mediated by Scavenger Receptor Class B Type 1 Results in Selective Sorting of HDL Cholesterol from Protein and Polarized Cholesterol Secretion* , 2001, The Journal of Biological Chemistry.

[44]  K. Luthman,et al.  Evaluation of dynamic polar molecular surface area as predictor of drug absorption: comparison with other computational and experimental predictors. , 1998, Journal of medicinal chemistry.

[45]  H. G. van Eijk,et al.  Quantification of Different Transferrin Receptor Pools in Primary Cultures of Porcine Blood‐Brain Barrier Endothelial Cells , 1995, Journal of neurochemistry.

[46]  B. Agranoff,et al.  Inhibition of Neutral Amino Acid Transport Across the Human Blood‐Brain Barrier by Phenylalanine , 1995, Journal of neurochemistry.

[47]  W. Pardridge,et al.  Receptor-Mediated Gene Targeting to Tissues In Vivo Following Intravenous Administration of Pegylated Immunoliposomes , 2001, Pharmaceutical Research.

[48]  J. Riordan,et al.  Synthetic and natural opiates interact with P-glycoprotein in multidrug-resistant cells. , 1993, The Journal of biological chemistry.

[49]  M. Mullan,et al.  β-Amyloid-mediated vasoactivity and vascular endothelial damage , 1996, Nature.

[50]  P J Lucassen,et al.  Multidrug resistance P-glycoprotein hampers the access of cortisol but not of corticosterone to mouse and human brain. , 2001, Endocrinology.

[51]  D. Breimer,et al.  Glucocorticoid and type 1 interferon interactions at the blood–brain barrier: relevance for drug therapies for multiple sclerosis , 2001, Neuroreport.

[52]  M. Snider,et al.  Membrane traffic in animal cells: cellular glycoproteins return to the site of Golgi mannosidase I , 1986, The Journal of cell biology.

[53]  D. M. Penny,et al.  The Hereditary Hemochromatosis Protein, HFE, Specifically Regulates Transferrin-mediated Iron Uptake in HeLa Cells* , 1999, The Journal of Biological Chemistry.

[54]  K. Zuideveld,et al.  Active efflux of the 5-HT(1A) receptor agonist flesinoxan via P-glycoprotein at the blood-brain barrier. , 2001, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[55]  P. Chikhale,et al.  Predominant functional activity of the large, neutral amino acid transporter (LAT1) isoform at the cerebrovasculature , 2001, Neuroscience Letters.

[56]  W. Pardridge,et al.  Neuroprotection in Transient Focal Brain Ischemia After Delayed Intravenous Administration of Brain-Derived Neurotrophic Factor Conjugated to a Blood-Brain Barrier Drug Targeting System , 2001, Stroke.

[57]  D. Breimer,et al.  Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood–brain barrier , 2001, AIDS.

[58]  A. Tall,et al.  The cellular biology of scavenger receptor class B type I , 2001, Current opinion in lipidology.

[59]  I. Trowbridge,et al.  Identification of the intermolecular disulfide bonds of the human transferrin receptor and its lipid‐attachment site. , 1987, The EMBO journal.

[60]  B. Penke,et al.  β-Amyloid (1–42) peptide impairs blood-brain barrier function after intracarotid infusion in rats , 1998, Neuroscience Letters.

[61]  G. Szakács,et al.  Functional Multidrug Resistance Protein (MRP1) Lacking the N-terminal Transmembrane Domain* , 1998, The Journal of Biological Chemistry.

[62]  Z. Qian,et al.  Brain iron transport and neurodegeneration. , 2001, Trends in molecular medicine.

[63]  M. Kool,et al.  The multidrug resistance protein family. , 1999, Biochimica et biophysica acta.

[64]  W. Löscher,et al.  In Vivo Evidence for P‐Glycoprotein–Mediated Transport of Phenytoin at the Blood–Brain Barrier of Rats , 2001, Epilepsia.

[65]  E. Wang,et al.  Cholesterol interaction with the daunorubicin binding site of P-glycoprotein. , 2000, Biochemical and biophysical research communications.

[66]  H. Kusuhara,et al.  Efflux transport systems for drugs at the blood-brain barrier and blood-cerebrospinal fluid barrier (Part 1). , 2001, Drug discovery today.

[67]  Hiroshi Kawabata,et al.  Transferrin Receptor 2-α Supports Cell Growth Both in Iron-chelated Cultured Cells and in Vivo * , 2000, The Journal of Biological Chemistry.

[68]  R. Steinman,et al.  Endocytosis and the recycling of plasma membrane , 1983, The Journal of cell biology.

[69]  H. Zinke,et al.  Expression of Apolipoprotein A‐I in Porcine Brain Endothelium In Vitro , 1994, Journal of neurochemistry.

[70]  I. Mellman.  Endocytosis and molecular sorting. , 1996, Annual review of cell and developmental biology.

[71]  M Danhof,et al.  Relevance of the Application of Pharmacokinetic-Pharmacodynamic Modelling Concepts in Drug Development , 1997, Clinical pharmacokinetics.

[72]  M. Vega,et al.  Identification, primary structure, and distribution of CLA-1, a novel member of the CD36/LIMPII gene family. , 1993, The Journal of biological chemistry.

[73]  T. Tsuruo,et al.  Possibility of the reversal of multidrug resistance and the avoidance of side effects by liposomes modified with MRK-16, a monoclonal antibody to P-glycoprotein. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[74]  W. T. Beck,et al.  Continued expression of vinca alkaloid resistance by CCRF-CEM cells after treatment with tunicamycin or pronase. , 1982, Cancer research.

[75]  Eiji Takeda,et al.  Identification and Functional Characterization of a Na+-independent Neutral Amino Acid Transporter with Broad Substrate Selectivity* , 1999, The Journal of Biological Chemistry.

[76]  J. Barrio,et al.  Distribution Volume of Radiolabeled Large Neutral Amino Acids in Brain Tissue , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[77]  D. Begley,et al.  Affinity for the P-Glycoprotein Efflux Pump at the Blood-Brain Barrier May Explain the Lack of CNS Side-Effects of Modern Antihistamines , 2001, Journal of drug targeting.

[78]  D. Gingras,et al.  P‐glycoprotein is localized in caveolae in resistant cells and in brain capillaries , 2000, FEBS letters.

[79]  O. Meijer,et al.  Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. , 1998, Endocrinology.

[80]  S. Bourgeois,et al.  Reversal of multidrug resistance by RU 486. , 1994, Cancer research.

[81]  P. Borst,et al.  What have we learnt thus far from mice with disrupted P-glycoprotein genes? , 1996, European journal of cancer.

[82]  D D Breimer,et al.  The blood-brain barrier in neuroinflammatory diseases. , 1997, Pharmacological reviews.

[83]  P. Morgan,et al.  Role of transport proteins in drug absorption, distribution and excretion , 2001, Xenobiotica; the fate of foreign compounds in biological systems.

[84]  A. Guyton,et al.  Textbook of Medical Physiology , 1961 .

[85]  W. Jefferies,et al.  Transferrin receptor on endothelium of brain capillaries , 1984, Nature.

[86]  H. Endou,et al.  The multispecific organic anion transporter (OAT) family , 2000, Pflügers Archiv.

[87]  L. Fenart,et al.  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 , 1998, Pharmaceutical Research.

[88]  P. Connell,et al.  The Class B, Type I Scavenger Receptor Promotes the Selective Uptake of High Density Lipoprotein Cholesterol Ethers into Caveolae* , 1999, The Journal of Biological Chemistry.

[89]  E. Taylor,et al.  Role of transferrin in iron uptake by the brain: a comparative study , 2004, Journal of Comparative Physiology B.

[90]  I. Pastan,et al.  Biochemistry of multidrug resistance mediated by the multidrug transporter. , 1993, Annual review of biochemistry.

[91]  E. Matsubara,et al.  The soluble form of Alzheimer's amyloid beta protein is complexed to high density lipoprotein 3 and very high density lipoprotein in normal human plasma. , 1994, Biochemical and biophysical research communications.

[92]  N J Abbott,et al.  Electrical resistance across the blood‐brain barrier in anaesthetized rats: a developmental study. , 1990, The Journal of physiology.

[93]  B. Zlokovic,et al.  Human blood-brain barrier receptors for Alzheimer's amyloid-beta 1- 40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. , 1998, The Journal of clinical investigation.

[94]  C. Janeway.  Approaching the asymptote? Evolution and revolution in immunology. , 1989, Cold Spring Harbor symposia on quantitative biology.

[95]  Luz Claudio,et al.  Ultrastructural features of the blood-brain barrier in biopsy tissue from Alzheimer's disease patients , 1995, Acta Neuropathologica.

[96]  M. Gumbleton.  Caveolae as potential macromolecule trafficking compartments within alveolar epithelium. , 2001, Advanced drug delivery reviews.

[97]  T. Terasaki,et al.  Restricted transport of 3'-azido-3'-deoxythymidine and dideoxynucleosides through the blood-brain barrier. , 1988, The Journal of infectious diseases.

[98]  P. Black,et al.  Central nervous system-immune system interactions: psychoneuroendocrinology of stress and its immune consequences , 1994, Antimicrobial Agents and Chemotherapy.

[99]  C. Cass,et al.  Recent advances in the molecular biology of nucleoside transporters of mammalian cells , 1998 .

[100]  A. Blokland,et al.  Apolipoprotein E Protects against Neuropathology Induced by a High-Fat Diet and Maintains the Integrity of the Blood-Brain Barrier during Aging , 2001, Laboratory Investigation.

[101]  H. Kobayashi,et al.  Adrenomedullin regulates blood–brain barrier functions in vitro , 2001, Neuroreport.

[102]  A. Moor,et al.  The blood-brain barrier and multiple sclerosis. , 1994, Biochemical pharmacology.

[103]  S. Bates,et al.  Differential modulation of P-glycoprotein transport by protein kinase inhibition. , 1993, Biochemistry.

[104]  R. Schwarcz,et al.  Facilitated brain uptake of 4‐chlorokynurenine and conversion to 7‐chlorokynurenic acid , 1996, Neuroreport.

[105]  K. Brouwer,et al.  Pharmacokinetic and Pharmacodynamic Implications of P‐glycoprotein Modulation , 2001, Pharmacotherapy.

[106]  T. Abe,et al.  Characterization of the Efflux Transport of 17β-Estradiol-d-17β-glucuronide from the Brain across the Blood-Brain Barrier , 2001 .

[107]  M Danhof,et al.  Characterization of an "in vitro" blood-brain barrier: effects of molecular size and lipophilicity on cerebrovascular endothelial transport rates of drugs. , 1988, The Journal of pharmacology and experimental therapeutics.

[108]  J. Testa,et al.  Analysis of the structure and expression pattern of MRP7 (ABCC10), a new member of the MRP subfamily. , 2001, Cancer letters.

[109]  P. Borst,et al.  Homozygous disruption of the murine MDR2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease , 1993, Cell.

[110]  M. Krieger,et al.  The other side of scavenger receptors: pattern recognition for host defense , 1997, Current opinion in lipidology.

[111]  P. Casey,et al.  Characterization of Prenylcysteines That Interact with P-glycoprotein and Inhibit Drug Transport in Tumor Cells (*) , 1995, The Journal of Biological Chemistry.

[112]  C. Peschle,et al.  Oxidative stress leads to a rapid alteration of transferrin receptor intravesicular trafficking. , 1998, Experimental cell research.

[113]  W. Pardridge.  Blood-Brain Barrier Carrier-Mediated Transport and Brain Metabolism of Amino Acids , 1998, Neurochemical Research.

[114]  M. Krieger,et al.  Scavenger receptor class B type I is a multiligand HDL receptor that influences diverse physiologic systems. , 2001, The Journal of clinical investigation.

[115]  W. Pardridge,et al.  Differential kinetics of transport of 2',3'-dideoxyinosine and adenosine via concentrative Na+ nucleoside transporter CNT2 cloned from rat blood-brain barrier. , 2001, The Journal of pharmacology and experimental therapeutics.

[116]  W. Pardridge.  BBB-Genomics: creating new openings for brain-drug targeting. , 2001, Drug discovery today.

[117]  R. Puertollano,et al.  The MAL proteolipid is necessary for the overall apical delivery of membrane proteins in the polarized epithelial Madin-Darby canine kidney and fischer rat thyroid cell lines. , 2000, Molecular biology of the cell.

[118]  Hans-Joachim Galla,et al.  An improved low-permeability in vitro-model of the blood–brain barrier: transport studies on retinoids, sucrose, haloperidol, caffeine and mannitol , 1999, Brain Research.

[119]  A. Tunkel,et al.  Pathogenesis and pathophysiology of bacterial meningitis , 1993, Clinical Microbiology Reviews.

[120]  E. Rubin,et al.  Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells , 1992, Cell.

[121]  M. Barrand,et al.  P‐glycoprotein expression in rat brain endothelial cells: 
evidence for regulation by transient oxidative stress , 2002, Journal of neurochemistry.

[122]  C Boesch,et al.  Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. , 1999, The Journal of clinical investigation.

[123]  N. Andrews,et al.  Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene , 1997, Nature genetics.

[124]  H. Takanaga,et al.  Blood—Brain Barrier Is Involved in the Efflux Transport of a Neuroactive Steroid, Dehydroepiandrosterone Sulfate, via Organic Anion Transporting Polypeptide 2 , 2000, Journal of neurochemistry.

[125]  Donald W. Miller,et al.  Expression of various multidrug resistance-associated protein (MRP) homologues in brain microvessel endothelial cells , 2000, Brain Research.

[126]  B. Sarkadi,et al.  An inventory of the human ABC proteins. , 1999, Biochimica et biophysica acta.

[127]  G. Pollack,et al.  Morphine Antinociception Is Enhanced in mdr1a Gene-Deficient Mice , 2000, Pharmaceutical Research.

[128]  B. McEwen,et al.  Neurotrophic and neuroprotective actions of estrogens and their therapeutic implications. , 2001, Annual review of pharmacology and toxicology.

[129]  Eiji Takeda,et al.  Expression Cloning and Characterization of a Transporter for Large Neutral Amino Acids Activated by the Heavy Chain of 4F2 Antigen (CD98)* , 1998, The Journal of Biological Chemistry.

[130]  M. Gottesman.  How cancer cells evade chemotherapy: sixteenth Richard and Hinda Rosenthal Foundation Award Lecture. , 1993, Cancer research.

[131]  A. Aguzzi,et al.  Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. , 2000, The Journal of pharmacology and experimental therapeutics.

[132]  M. Hebert,et al.  Diltiazem Increases Tacrolimus Concentrations , 1999, The Annals of pharmacotherapy.

[133]  C. K. Pearson,et al.  Stage-specific distribution of P-glycoprotein in first-trimester and full-term human placenta , 1994, The Histochemical Journal.

[134]  I. Tamai,et al.  Transporter-mediated permeation of drugs across the blood-brain barrier. , 2000, Journal of pharmaceutical sciences.

[135]  M. Melamed,et al.  Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[136]  I. Pastan,et al.  Biochemical, cellular, and pharmacological aspects of the multidrug transporter. , 1999, Annual review of pharmacology and toxicology.

[137]  de Lange EC,et al.  Microdialysis for pharmacokinetic analysis of drug transport to the brain. , 1999, Advanced drug delivery reviews.

[138]  D. Housman,et al.  The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues , 1989, Molecular and cellular biology.

[139]  J. Kooij,et al.  ADHD bij volwassenen , 2001, Neuropraxis.

[140]  R. Janzer,et al.  Astrocytes induce blood–brain barrier properties in endothelial cells , 1987, Nature.

[141]  S. Cole,et al.  Reconstitution of ATP-dependent Leukotriene C4 Transport by Co-expression of Both Half-molecules of Human Multidrug Resistance Protein in Insect Cells* , 1996, The Journal of Biological Chemistry.

[142]  J. Beijnen,et al.  P-glycoprotein limits oral availability, brain, and fetal penetration of saquinavir even with high doses of ritonavir. , 2001, Molecular pharmacology.

[143]  Y. Hannun,et al.  Regulation of volume‐activated chloride channels by P‐glycoprotein: phosphorylation has the final say! , 2000, The Journal of physiology.