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Choroid Plexus and Drug Removal Mechanisms

  • Review Article
  • Theme: Celebrating Women in the Pharmaceutical Sciences
  • Published:
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Abstract

Timely and efficient removal of xenobiotics and metabolites from the brain is crucial in maintaining the homeostasis and normal function of the brain. The choroid plexus (CP) forms the blood-cerebrospinal fluid barrier and vitally removes drugs and wastes from the brain through several co-existing clearance mechanisms. The CP epithelial (CPE) cells synthesize and secrete the cerebrospinal fluid (CSF). As the CSF passes through the ventricular and subarachnoid spaces and eventually drains into the general circulation, it collects and removes drugs, toxins, and metabolic wastes from the brain. This bulk flow of the CSF serves as a default and non-selective pathway for the removal of solutes and macromolecules from the brain interstitium. Besides clearance by CSF bulk flow, the CPE cells express several multispecific membrane transporters to actively transport substrates from the CSF side into the blood side. In addition, several phase I and II drug-metabolizing enzymes are expressed in the CPE cells, which enzymatically inactivate a broad spectrum of reactive or toxic substances. This review summarizes our current knowledge of the functional characteristics and key contributors to the various clearance pathways in the CP-CSF system, overviewing recent developments in our understanding of CSF flow dynamics and the functional roles of CP uptake and efflux transporters in influencing CSF drug concentrations.

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Abbreviations

ABC:

ATP-binding cassette

BBB:

blood-brain barrier

BCSFB:

blood-cerebrospinal fluid barrier

BCRP:

breast cancer resistance protein

CNS:

central nervous system

CP:

choroid plexus

CYP:

cytochrome P450

CPE Cells:

choroid plexus epithelial cells

CSF:

cerebrospinal fluid

ISF:

interstitial fluid

GST:

glutathione S-transferase

fluo-cAMP:

fluorescein-cyclic AMP

Kpuu :

unbound partition coefficient

MAO:

monoamine oxidase

OAT:

organic anion transporter

OCT:

organic cation transporter

PEPT2:

Peptide transporter 2

PMAT:

plasma membrane monoamine transporter

MRP:

multidrug resistance-associated protein

P-gp:

P-glycoprotein

SLC:

solute carrier

SULT:

sulfotransferase

UGT:

UDP-glucuronosyltransferase

References

  1. Lun MP, Monuki ES, Lehtinen MK. Development and functions of the choroid plexus-cerebrospinal fluid system. Nat Rev Neurosci. 2015;16(8):445–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fame RM, Cortés-Campos C, Sive HL. Brain ventricular system and cerebrospinal fluid development and function: light at the end of the tube: a primer with latest insights. Bioessays. 2020;42(3):e1900186.

    Article  PubMed  Google Scholar 

  3. Betts JG, Young KA, Wise JA, Johnson E, Poe B, Kruse DH, et al. Circulation and the central nervous system. In: Anatomy and physiology. OpenStax: Houston; 2013.

    Google Scholar 

  4. Spector R, Keep RF, Snodgrass SR, Smith QR, Johanson CE. A balanced view of choroid plexus structure and function: focus on adult humans. Exp Neurol. 2015;267:78–86.

    Article  PubMed  Google Scholar 

  5. Damkier HH, Brown PD, Praetorius J. Epithelial pathways in choroid plexus electrolyte transport. Physiology. 2010;25(4):239–49.

    Article  CAS  PubMed  Google Scholar 

  6. Davson H, Purvis C. Cryoscopic apparatus suitable for studies on aqueous humour and cerebro-spinal fluid. J Physiol. 1954;124:1–47 12P.

    CAS  PubMed  Google Scholar 

  7. Welch K, Sadler K. Electrical potentials of choroid plexus of the rabbit. J Neurosurg. 1965;22(4):344–51.

    Article  CAS  PubMed  Google Scholar 

  8. Wolburg H, Paulus W. Choroid plexus: biology and pathology. Acta Neuropathol. 2010;119(1):75–88.

    Article  PubMed  Google Scholar 

  9. Prinz M, Priller J. The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci. 2017;20(2):136–44.

    Article  CAS  PubMed  Google Scholar 

  10. Prinz M, Priller J, Sisodia SS, Ransohoff RM. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci. 2011;14(10):1227–35.

    Article  CAS  PubMed  Google Scholar 

  11. Schwartz M, Baruch K. The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus. EMBO J. 2014;33(1):7–22.

    Article  CAS  PubMed  Google Scholar 

  12. Davson H, Welch K, Segal MB. Physiology and pathophysiology of the cerebrospinal fluid. Edinburgh–London: Churchill Livingstone; 1987.

    Google Scholar 

  13. Davson H. Segal MB. Physiology of the CSF and blood-brain barriers. Boca Raton, FL: CRC press; 1996.

  14. Spector R, Robert Snodgrass S, Johanson CE. A balanced view of the cerebrospinal fluid composition and functions: focus on adult humans. Exp Neurol. 2015;273:57–68.

    Article  CAS  PubMed  Google Scholar 

  15. Dawson RMC, Freinkel N. The distribution of free mesoinositol in mammalian tissues, including some observations on the lactating rat. Biochem J. 1961;78(3):606–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. de Rougemont J, Ames A, Nesbett FB, Hofmann HF. Fluid formed by choroid plexus: a technique for its collection and a comparison of its electrolyte composition with serum and cisternal fluids. J Neurophysiol. 1960;23(5):485–95.

    Article  PubMed  Google Scholar 

  17. Johanson CE, Stopa EG, McMillan PN. The Blood-Cerebrospinal Fluid Barrier: Structure and Functional Significance. In: Nag S, editor. The Blood-Brain and Other Neural Barriers. New York: Springer; 2011. p. 101–31.

    Chapter  Google Scholar 

  18. Herndon RM, Brumback RA. The Cerebrospinal Fluid. Boston/Dordrecht/London: Kluwer Academic Publishers; 2012.

    Google Scholar 

  19. Thompson EJ, The CSF. Proteins: A Biochemical Approach. Amsterdam: Elsevier; 1988. p. 9–26.

    Google Scholar 

  20. Sakka L, Coll G, Chazal J. Anatomy and physiology of cerebrospinal fluid. Eur Ann Otorhinolaryngol Head Neck Dis. 2011;128(6):309–16.

    Article  CAS  PubMed  Google Scholar 

  21. Nilsson C, Stahlberg F, Thomsen C, Henriksen O, Herning M, Owman C. Circadian variation in human cerebrospinal fluid production measured by magnetic resonance imaging. Am J Physiol Integr Comp Physiol. 1992;262(1):R20–4.

    Article  CAS  Google Scholar 

  22. Dreha-Kulaczewski S, Joseph AA, Merboldt K-D, Ludwig H-C, Gärtner J, Frahm J. Inspiration is the major regulator of human CSF flow. J Neurosci. 2015;35(6):2485–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bateman GA, Brown KM. The measurement of CSF flow through the aqueduct in normal and hydrocephalic children: from where does it come, to where does it go? Childs Nerv Syst. 2012;28(1):55–63.

    Article  PubMed  Google Scholar 

  24. Rubin RC, Henderson ES, Ommaya AK, Walker MD, Rall DP. The production of cerebrospinal fluid in man and its modification by acetazolamide. J Neurosurg. 1966;25(4):430–6.

    Article  CAS  PubMed  Google Scholar 

  25. Cutler RW, Page L, Galicich J, Watters GV. Formation and absorption of cerebrospinal fluid in man. Brain. 1968;91(4):707–20.

    Article  CAS  PubMed  Google Scholar 

  26. Lorenzo AV, Page LK, Watters GV. Relationship between cerebrospinal fluid formation, absorption and pressure in human hydrocephalus. Brain. 1970;93(4):679–92.

    Article  CAS  PubMed  Google Scholar 

  27. Preston JE. Ageing choroid plexus-cerebrospinal fluid system. Microsc Res Tech. 2001;52(1):31–7.

    Article  CAS  PubMed  Google Scholar 

  28. May C, Kaye JA, Atack JR, Schapiro MB, Friedland RP, Rapoport SI. Cerebrospinal fluid production is reduced in healthy aging. Neurology. 1990;40(3 Part 1):500 LP – 500.

    Article  Google Scholar 

  29. Chen CPC, Chen RL, Preston JE. The influence of cerebrospinal fluid turnover on age-related changes in cerebrospinal fluid protein concentrations. Neurosci Lett. 2010;476(3):138–41.

    Article  CAS  PubMed  Google Scholar 

  30. Chiu C, Miller MC, Caralopoulos IN, Worden MS, Brinker T, Gordon ZN, et al. Temporal course of cerebrospinal fluid dynamics and amyloid accumulation in the aging rat brain from three to thirty months. Fluids Barriers CNS. 2012;9(1):3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Silverberg GD, Heit G, Huhn S, Jaffe RA, Chang SD. Bronte–Stewart H, et al. The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer’s type. Neurology. 2001;57(10):1763–6.

    Article  CAS  PubMed  Google Scholar 

  32. de Leon MJ, Li Y, Okamura N, Tsui WH, Saint-Louis LA, Glodzik L, et al. Cerebrospinal fluid clearance in alzheimer disease measured with dynamic PET. J Nucl Med. 2017;58(9):1471–6.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Schubert JJ, Veronese M, Marchitelli L, Bodini B, Tonietto M, Stankoff B, et al. Dynamic 11C-PiB PET shows cerebrospinal fluid flow alterations in Alzheimer disease and multiple sclerosis. J Nucl Med. 2019;60(10):1452–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Alperin N, Lee SH, Sivaramakrishnan A, Hushek SG. Quantifying the effect of posture on intracranial physiology in humans by MRI flow studies. J Magn Reson Imaging. 2005;22(5):591–6.

    Article  PubMed  Google Scholar 

  35. Fultz NE, Bonmassar G, Setsompop K, Stickgold RA, Rosen BR, Polimeni JR, et al. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science (80- ). 2019;366(6465):628–31.

    Article  CAS  Google Scholar 

  36. Grubb S, Lauritzen M. Deep sleep drives brain fluid oscillations. Science. 2019;366(6465):572–3.

    Article  CAS  PubMed  Google Scholar 

  37. Abbott NJ. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int. 2004;45(4):545–52.

    Article  CAS  PubMed  Google Scholar 

  38. Jessen NA, Munk ASF, Lundgaard I, Nedergaard M. The glymphatic system: a beginner’s guide. Neurochem Res. 2015;40(12):2583–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pardridge WM. CSF, blood-brain barrier, and brain drug delivery. Expert Opin Drug Deliv. 2016;13(7):963–75.

    Article  CAS  PubMed  Google Scholar 

  40. Davson H, Segal MB. The effects of some inhibitors and accelerators of sodium transport on the turnover of 22Na in the cerebrospinal fluid and the brain. J Physiol. 1970;209(1):131–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Oldendorf WH, Davson H. brain extracellular space and the sink action of cerebrospinal fluid: measurement of rabbit brain extracellular space using sucrose labeled with carbon 14. Arch Neurol. 1967;17(2):196–205.

    Article  CAS  PubMed  Google Scholar 

  42. Abbott NJ, Pizzo ME, Preston JE, Janigro D, Thorne RG. The role of brain barriers in fluid movement in the CNS: is there a “glymphatic” system? Acta Neuropathol. 2018;135(3):387–407.

    Article  CAS  PubMed  Google Scholar 

  43. Cserr HF, Cooper DN, Suri PK, Patlak CS. Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am J Physiol Physiol. 1981;240(4):F319–28.

    Article  CAS  Google Scholar 

  44. Cserr HF, Cooper DN, Milhorat TH. Flow of cerebral interstitial fluid as indicated by the removal of extracellular markers from rat caudate nucleus. Exp Eye Res. 1977;25:461–73.

    Article  PubMed  Google Scholar 

  45. Plog BA, Nedergaard M. The glymphatic system in central nervous system health and disease: past, present, and future. Annu Rev Pathol Mech Dis. 2018;13(1):379–94.

    Article  CAS  Google Scholar 

  46. Wang M, Liao Y, Venkataraman A, Plog BA, Nedergaard M, Deane R, et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci. 2013;33(46):18190–9.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, et al. Sleep drives metabolite clearance from the adult brain. Science (80- ). 2013;342(6156):373–7.

    Article  CAS  Google Scholar 

  48. Smith AJ, Yao X, Dix JA, Jin B-J, Verkman AS. Test of the “glymphatic” hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma. Huguenard J, editor. Elife. 2017;6:e27679.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Mestre H, Hablitz LM, Xavier ALR, Feng W, Zou W, Pu T, et al. Aquaporin-4-dependent glymphatic solute transport in the rodent brain. Kleinfeld D, Morrison SJ, editors. Elife. 2018;7:e40070.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Wolak DJ, Thorne RG. Diffusion of macromolecules in the brain: implications for drug delivery. Mol Pharm. 2013;10(5):1492–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Holter KE, Kehlet B, Devor A, Sejnowski TJ, Dale AM, Omholt SW, et al. Interstitial solute transport in 3D reconstructed neuropil occurs by diffusion rather than bulk flow. Proc Natl Acad Sci. 2017;114(37):9894–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Giacomini KM, Huang S-M, Tweedie DJ, Benet LZ, Brouwer KLR, Chu X, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215–36.

    Article  CAS  PubMed  Google Scholar 

  53. Wagner DJ, Hu T, Wang J. Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics. Pharmacol Res. 2016;111:237–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Giacomini KM, Huang S-M, Tweedie DJ, Benet LZ, Brouwer KLR, Chu X, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215–36.

    Article  CAS  PubMed  Google Scholar 

  55. Lin L, Yee SW, Kim RB, Giacomini KM. SLC transporters as therapeutic targets: emerging opportunities. Nat Rev Drug Discov. 2015;14(8):543–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dahlin A, Royall J, Hohmann JG, Wang J. Expression profiling of the solute carrier gene family in the mouse brain. J Pharmacol Exp Ther. 2009;329(2):558–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ho HTB, Dahlin A, Wang J. Expression Profiling of Solute Carrier Gene Families at the Blood-CSF Barrier. Front Pharmacol. 2012;3:154.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Choudhuri S, Cherrington NJ, Li N, Klaassen CD. Constitutive expression of various xenobiotic and endobiotic transporter mRNAs in the choroid plexus of rats. Drug Metab Dispos. 2003;31(11):1337–45.

    Article  CAS  PubMed  Google Scholar 

  59. Uchida Y, Zhang Z, Tachikawa M, Terasaki T. Quantitative targeted absolute proteomics of rat blood-cerebrospinal fluid barrier transporters: comparison with a human specimen. J Neurochem. 2015;134(6):1104–15.

    Article  CAS  PubMed  Google Scholar 

  60. Braun C, Sakamoto A, Fuchs H, Ishiguro N, Suzuki S, Cui Y, et al. Quantification of transporter and receptor proteins in dog brain capillaries and choroid plexus: relevance for the distribution in brain and CSF of selected BCRP and P-gp substrates. Mol Pharm. 2017;14(10):3436–47.

    Article  CAS  PubMed  Google Scholar 

  61. Uchida Y, Goto R, Takeuchi H, Łuczak M, Usui T, Tachikawa M, et al. Abundant expression of OCT2, MATE1, OAT1, OAT3, PEPT2, BCRP, MDR1, and xCT transporters in blood-arachnoid barrier of pig and polarized localizations at CSF- and blood-facing plasma membranes. Drug Metab Dispos. 2020;48(2):135–45.

    Article  CAS  PubMed  Google Scholar 

  62. Akanuma S, Kubo Y, Hosoya K. Techniques for Evaluating Efflux Transport of Radiolabeled Drugs and Compounds from the Cerebrospinal Fluid Across the Blood-Cerebrospinal Fluid Barrier. In: Barichello T, editor. Blood-Brain Barrier. New York, NY: Springer New York; 2019. p. 231–48. 

  63. Kläs J, Wolburg H, Terasaki T, Fricker G, Reichel V. Characterization of immortalized choroid plexus epithelial cell lines for studies of transport processes across the blood-cerebrospinal fluid barrier. Cerebrospinal Fluid Res. 2010;7(1):11.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Pellegrini L, Bonfio C, Chadwick J, Begum F, Skehel M, Lancaster MA. Human CNS barrier-forming organoids with cerebrospinal fluid production. Science (80- ). 2020;369(6500):eaaz5626.

    Article  CAS  Google Scholar 

  65. Rao VV, Dahlheimer JL, Bardgett ME, Snyder AZ, Finch RA, Sartorelli AC, et al. 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. 1999;96(7):3900–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gao B, Stieger B, Noé B, Fritschy J-M, Meier PJ. Localization of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroid plexus epithelium of rat brain. J Histochem Cytochem. 1999;47(10):1255–63.

    Article  CAS  PubMed  Google Scholar 

  67. Gazzin S, Strazielle N, Schmitt C, Fevre-Montange M, Ostrow JD, Tiribelli C, et al. Differential expression of the multidrug resistance-related proteins ABCb1 and ABCc1 between blood-brain interfaces. J Comp Neurol. 2008;510(5):497–507.

    Article  CAS  PubMed  Google Scholar 

  68. Morris ME, Rodriguez-Cruz V, Felmlee MA. SLC and ABC Transporters: Expression, Localization, and Species Differences at the Blood-Brain and the Blood-Cerebrospinal Fluid Barriers. AAPS J. 2017;19(5):1317–31.

    Article  PubMed  Google Scholar 

  69. Felmlee MA, Jones RS, Rodriguez-Cruz V, Follman KE, Morris ME. Monocarboxylate transporters (SLC16): function, regulation, and role in health and disease. Daws LC, editor. Pharmacol Rev. 2020;72(2):466–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Pritchard JB. Intracellular alpha-ketoglutarate controls the efficacy of renal organic anion transport. J Pharmacol Exp Ther. 1995;274(3):1278–84.

    CAS  PubMed  Google Scholar 

  71. Nigam SK, Bush KT, Martovetsky G, Ahn S-Y, Liu HC, Richard E, et al. The organic anion transporter (OAT) family: a systems biology perspective. Physiol Rev. 2015;95(1):83–123.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Nagata Y, Kusuhara H, Endou H, Sugiyama Y. Expression and functional characterization of rat organic anion transporter 3 (rOat3) in the choroid plexus. Mol Pharmacol. 2002;61(5):982–8.

    Article  CAS  PubMed  Google Scholar 

  73. Cha SH, Sekine T, Fukushima J, Kanai Y, Kobayashi Y, Goya T, et al. Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001;59(5):1277–86.

    Article  CAS  PubMed  Google Scholar 

  74. Matsumoto S, Yoshida K, Ishiguro N, Maeda T, Tamai I. Involvement of rat and human organic anion transporter 3 in the renal tubular secretion of topotecan [(S)-9-dimethylaminomethyl-10-hydroxy-camptothecin hydrochloride]. J Pharmacol Exp Ther. 2007;322(3):1246–52.

    Article  CAS  PubMed  Google Scholar 

  75. Takeda M, Khamdang S, Narikawa S, Kimura H, Kobayashi Y, Yamamoto T, et al. Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther. 2002;300(3):918–24.

    Article  CAS  PubMed  Google Scholar 

  76. Tahara H, Shono M, Kusuhara H, Kinoshita H, Fuse E, Takadate A, et al. Molecular cloning and functional analyses of OAT1 and OAT3 from cynomolgus monkey kidney. Pharm Res. 2005;22(4):647–60.

    Article  CAS  PubMed  Google Scholar 

  77. Ueo H, Motohashi H, Katsura T, Inui K. Human organic anion transporter hOAT3 is a potent transporter of cephalosporin antibiotics, in comparison with hOAT1. Biochem Pharmacol. 2005;70(7):1104–13.

    Article  CAS  PubMed  Google Scholar 

  78. Yin J, Wagner DJ, Prasad B, Isoherranen N, Thummel KE, Wang J. Renal secretion of hydrochlorothiazide involves organic anion transporter 1/3, organic cation transporter 2, and multidrug and toxin extrusion protein 2-K. Am J Physiol Physiol. 2019;317(4):F805–14.

    Article  CAS  Google Scholar 

  79. Ebner T, Ishiguro N, Taub ME. The use of transporter probe drug cocktails for the assessment of transporter-based drug-drug interactions in a clinical setting - proposal of a four component transporter cocktail. J Pharm Sci. 2015;104(9):3220–8.

    Article  CAS  PubMed  Google Scholar 

  80. Duan H, Wang J. Impaired monoamine and organic cation uptake in choroid plexus in mice with targeted disruption of the plasma membrane monoamine transporter (Slc29a4) gene. J Biol Chem. 2013;288(5):3535–44.

    Article  CAS  PubMed  Google Scholar 

  81. Zhou M, Xia L, Wang J. Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab Dispos. 2007;35(10):1956–62.

    Article  CAS  PubMed  Google Scholar 

  82. Mimura Y, Yasujima T, Ohta K, Inoue K, Yuasa H. Functional identification of plasma membrane monoamine transporter (PMAT/SLC29A4) as an atenolol transporter sensitive to flavonoids contained in apple juice. J Pharm Sci. 2017;106(9):2592–8.

    Article  CAS  PubMed  Google Scholar 

  83. Shu C, Shen H, Teuscher NS, Lorenzi PJ, Keep RF, Smith DE. Role of PEPT2 in peptide/mimetic trafficking at the blood-cerebrospinal fluid barrier: studies in rat choroid plexus epithelial cells in primary culture. J Pharmacol Exp Ther. 2002;301(3):820–9.

    Article  CAS  PubMed  Google Scholar 

  84. Song F, Hu Y, Jiang H, Smith DE. Species differences in human and rodent PEPT2-mediated transport of glycylsarcosine and cefadroxil in pichia pastoris transformants. Drug Metab Dispos. 2017;45(2):130–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Li M, Anderson GD, Phillips BR, Kong W, Shen DD, Wang J. Interactions of amoxicillin and cefaclor with human renal organic anion and peptide transporters. Drug Metab Dispos. 2006;34(4):547–55.

    Article  CAS  PubMed  Google Scholar 

  86. Zaman GJ, Flens MJ, van Leusden MR, de Haas M, Mülder HS, Lankelma J, et al. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proc Natl Acad Sci. 1994;91(19):8822–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zeng H, Chen Z-S, Belinsky MG, Rea PA, Kruh GD. Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1. Cancer Res. 2001;61(19):7225–32.

    CAS  PubMed  Google Scholar 

  88. Knauer MJ, Urquhart BL, Meyer zu Schwabedissen HE, Schwarz UI, Lemke CJ, Leake BF, et al. Human skeletal muscle drug transporters determine local exposure and toxicity of statins. Circ Res. 2010;106(2):297–306.

    Article  CAS  PubMed  Google Scholar 

  89. van der Sandt IC, Vos CM, Nabulsi L, Blom-Roosemalen MC, Voorwinden HH, de Boer AG, et al. Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood-brain barrier. AIDS. 2001;15(4):483–91.

    Article  PubMed  Google Scholar 

  90. de Waart DR, van de Wetering K, Kunne C, Duijst S, Paulusma CC, Oude Elferink RPJ. Oral availability of cefadroxil depends on ABCC3 and ABCC4. Drug Metab Dispos. 2012;40(3):515–21.

    Article  PubMed  Google Scholar 

  91. Leggas M, Adachi M, Scheffer GL, Sun D, Wielinga P, Du G, et al. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol Cell Biol. 2004;24(17):7612–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Chen Z-S, Lee K, Walther S, Raftogianis RB, Kuwano M, Zeng H, et al. Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system. Cancer Res. 62(11):3144–50.

  93. Tian Q, Zhang J, Chan SY. Chin Tan, Theresa M., Duan W, et al. Topotecan is a substrate for multidrug resistance associated protein 4. Curr Drug Metab. 2006;7(1):105–18.

    Article  CAS  PubMed  Google Scholar 

  94. Chen ZS, Lee K, Kruh GD. Transport of cyclic nucleotides and estradiol 17-beta-D-glucuronide by multidrug resistance protein 4. Resistance to 6-mercaptopurine and 6-thioguanine. J Biol Chem. 2001;276(36):33747–54.

    Article  CAS  PubMed  Google Scholar 

  95. Imaoka T, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y. Functional involvement of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir. Mol Pharmacol. 2007;71(2):619–27.

    Article  CAS  PubMed  Google Scholar 

  96. Ci L, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y. Involvement of MRP4 (ABCC4) in the luminal efflux of ceftizoxime and cefazolin in the kidney. Mol Pharmacol. 2007;71(6):1591–7.

    Article  CAS  PubMed  Google Scholar 

  97. Hasegawa Maki, Kusuhara Hiroyuki, Adachi Masashi, Schuetz John D, Takeuchi Kenji, Sugiyama Yuichi. Multidrug resistance-associated protein 4 is involved in the urinary excretion of hydrochlorothiazide and furosemide. J Am Soc Nephrol. 2007;18(1):37–45.

    Article  CAS  PubMed  Google Scholar 

  98. VanWert AL, Bailey RM, Sweet DH. Organic anion transporter 3 (Oat3/Slc22a8) knockout mice exhibit altered clearance and distribution of penicillin G. Am J Physiol Physiol. 2007;293(4):F1332–41.

    Article  CAS  Google Scholar 

  99. VanWert AL, Sweet DH. Impaired Clearance of methotrexate in organic anion transporter 3 (Slc22a8) knockout mice: a gender specific impact of reduced folates. Pharm Res. 2008;25(2):453–62.

    Article  CAS  PubMed  Google Scholar 

  100. Pappenheimer JR, Heisey SR, Jordan EF. Active transport of diodrast and phenolsulfonphthalein from cerebrospinal fluid to blood. Am J Physiol Content. 1961;200(1):1–10.

    Article  CAS  Google Scholar 

  101. Fishman RA. Blood-brain and CSF barriers to penicillin and related organic acids. Arch Neurol. 1966;15(2):113–24.

    Article  CAS  PubMed  Google Scholar 

  102. Sweet DH, Wolff NA, Pritchard JB. Expression cloning and characterization of ROAT1: the basolateral organic anion transporter in rat kidney. J Biol Chem. 1997;272(48):30088–95.

    Article  CAS  PubMed  Google Scholar 

  103. Sekine T, Watanabe N, Hosoyamada M, Kanai Y, Endou H. Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem. 1997;272(30):18526–9.

    Article  CAS  PubMed  Google Scholar 

  104. Bode U, Magrath IT, Bleyer WA, Poplack DG, Glaubiger DL. Active Transport of Methotrexate from Cerebrospinal Fluid in Humans. Cancer Res. 1980;40(7):2184–7.

    CAS  PubMed  Google Scholar 

  105. Sweet DH, Miller DS, Pritchard JB, Fujiwara Y, Beier DR, Nigam SK. Impaired Organic Anion Transport in Kidney and Choroid Plexus of Organic Anion Transporter 3 (Oat3 (Slc22a8)) Knockout Mice. J Biol Chem. 2002;277(30):26934–43.

    Article  CAS  PubMed  Google Scholar 

  106. Sykes D, Sweet DH, Lowes S, Nigam SK, Pritchard JB, Miller DS, et al. Organic anion transport in choroid plexus from wild-type and organic anion transporter 3 (Slc22a8)-null mice. Am J Physiol Ren Physiol. 2004;286(5):F972–8.

    Article  CAS  Google Scholar 

  107. Liu W, Liang R, Ramamoorthy S, Fei Y-J, Ganapathy ME, Hediger MA, et al. Molecular cloning of PEPT 2, a new member of the H+/peptide cotransporter family, from human kidney. Biochim Biophys Acta Biomembr. 1995;1235(2):461–6.

    Article  Google Scholar 

  108. Kamal MA, Keep RF, Smith DE. Role and relevance of PEPT2 in drug disposition, dynamics, and toxicity. Drug Metab Pharmacokinet. 2008;23(4):236–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Smith DE, Clémençon B, Hediger MA. Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications. Mol Asp Med. 2013;34(2):323–36.

    Article  CAS  Google Scholar 

  110. Ocheltree SM, Shen H, Hu Y, Keep RF, Smith DE. Role and relevance of peptide transporter 2 (PEPT2) in the kidney and choroid plexus: in vivo studies with glycylsarcosine in wild-type and PEPT2 knockout mice. J Pharmacol Exp Ther. 2005;315(1):240–7.

    Article  CAS  PubMed  Google Scholar 

  111. Shen H, Ocheltree SM, Hu Y, Keep RF, Smith DE. Impact of genetic knockout of PEPT2 on cefadroxil pharmacokinetics, renal tubular reabsorption, and brain penetration in mice. Drug Metab Dispos. 2007;35(7):1209–16.

    Article  PubMed  Google Scholar 

  112. Kamal MA, Jiang H, Hu Y, Keep RF, Smith DE. Influence of genetic knockout of Pept2 on the in vivo disposition of endogenous and exogenous carnosine in wild-type and Pept2 null mice. Am J Physiol Integr Comp Physiol. 2009;296(4):R986–91.

    Article  CAS  Google Scholar 

  113. Shen H, Smith DE, Keep RF, Brosius FC. Immunolocalization of the proton-coupled oligopeptide transporter PEPT2 in developing rat brain. Mol Pharm. 2004;1(4):248–56.

    Article  CAS  PubMed  Google Scholar 

  114. Shen H, Smith DE, Keep RF, Xiang J, Brosius FC. Targeted disruption of the PEPT2 gene markedly reduces dipeptide uptake in choroid plexus. J Biol Chem. 2003;278(7):4786–91.

    Article  CAS  PubMed  Google Scholar 

  115. Shen H, Keep RF, Hu Y, Smith DE. PEPT2 (Slc15a2)-mediated unidirectional transport of cefadroxil from cerebrospinal fluid into choroid plexus. J Pharmacol Exp Ther. 2005;315(3):1101–8.

    Article  CAS  PubMed  Google Scholar 

  116. Chen X, Keep RF, Liang Y, Zhu H-J, Hammarlund-Udenaes M, Hu Y, et al. Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: a microdialysis study. Biochem Pharmacol. 2017;131:89–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Engel K, Zhou M, Wang J. Identification and characterization of a novel monoamine transporter in the human brain. J Biol Chem. 2004;279(48):50042–9.

    Article  CAS  PubMed  Google Scholar 

  118. Wang J. The plasma memebrane monoamine transporter (PMAT): structure, function, and role in organic cation disposition. Clin Pharmacol Ther. 2016;100(5):489–99.

    Article  CAS  PubMed  Google Scholar 

  119. Foti RS, Swaan PW, Wang J, Duan H, Pan Y, Hu T. Potent and selective inhibition of plasma membrane monoamine transporter by HIV protease inhibitors. Drug Metab Dispos. 2015;43(11):1773–80.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Itagaki S, Ganapathy V, Ho HTB, Zhou M, Babu E, Wang J. Electrophysiological characterization of the polyspecific organic cation transporter plasma membrane monoamine transporter. Drug Metab Dispos. 2012;40(6):1138–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Duan H, Wang J. Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J Pharmacol Exp Ther. 2010;335(3):743–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Xia L, Engel K, Zhou M, Wang J. Membrane localization and pH-dependent transport of a newly cloned organic cation transporter (PMAT) in kidney cells. Am J Physiol Physiol. 2007;292(2):F682–90.

    Article  CAS  Google Scholar 

  123. Sweet DH, Miller DS, Pritchard JB. Ventricular choline transport: a role for organic cation transporter 2 expressed in choroid plexus. J Biol Chem. 2001;276(45):41611–9.

    Article  CAS  PubMed  Google Scholar 

  124. Miller DS, Villalobos AR, Pritchard JB. Organic cation transport in rat choroid plexus cells studied by fluorescence microscopy. Am J Physiol Physiol. 1999;276(4):C955–68.

    Article  CAS  Google Scholar 

  125. Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science (80- ). 1992;258(5088):1650–4.

    Article  CAS  Google Scholar 

  126. Cole SPC. Targeting multidrug resistance protein 1 (MRP1, ABCC1): past, present, and future. Annu Rev Pharmacol Toxicol. 2014;54(1):95–117.

    Article  CAS  PubMed  Google Scholar 

  127. Lu JF, Pokharel D, Bebawy M. MRP1 and its role in anticancer drug resistance. Drug Metab Rev. 2015;47(4):406–19.

    Article  CAS  PubMed  Google Scholar 

  128. Semsei AF, Erdelyi DJ, Ungvari I, Csagoly E, Hegyi MZ, Kiszel PS, et al. ABCC1 polymorphisms in anthracycline-induced cardiotoxicity in childhood acute lymphoblastic leukaemia. Cell Biol Int. 2012;36(1):79–86.

    Article  CAS  PubMed  Google Scholar 

  129. Krause MS, Oliveira LP Jr, Silveira EMS, Vianna DR, Rossato JS, Almeida BS, et al. MRP1/GS-X pump ATPase expression: is this the explanation for the cytoprotection of the heart against oxidative stress-induced redox imbalance in comparison to skeletal muscle cells? Cell Biochem Funct. 2007;25(1):23–32.

    Article  CAS  PubMed  Google Scholar 

  130. Leszek W, Bettina K, Markus S, Gregor S, Albrecht S, Albert R, et al. NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation. 2005;112(24):3754–62.

    Article  Google Scholar 

  131. Wijnholds J, de Lange ECM, Scheffer GL, van den Berg D-J, Mol CAAM, van der Valk M, et al. Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier. J Clin Invest. 2000;105(3):279–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kool M, De Haas M, Scheffer GL, Scheper RJ, Van Eijk MJT, Juijn JA, et al. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res. 1997;57(16):3537–47.

    CAS  PubMed  Google Scholar 

  133. Russel FGM, Koenderink JB, Masereeuw R. Multidrug resistance protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signalling molecules. Trends Pharmacol Sci. 2008;29(4):200–7.

    Article  CAS  PubMed  Google Scholar 

  134. Nies AT, Jedlitschky G, König J, Herold-Mende C, Steiner HH, Schmitt H-P, et al. Expression and immunolocalization of the multidrug resistance proteins, MRP1–MRP6 (ABCC1–ABCC6), in human brain. Neuroscience. 2004;129(2):349–60.

    Article  CAS  PubMed  Google Scholar 

  135. Zamek-Gliszczynski MJ, Taub ME, Chothe PP, Chu X, Giacomini KM, Kim RB, et al. Transporters in drug development: 2018 ITC recommendations for transporters of emerging clinical importance. Clin Pharmacol Ther. 2018;104(5):890–9.

    Article  PubMed  Google Scholar 

  136. Reichel V, Kläs J, Fricker G, Masereeuw R. Fluo-cAMP is transported by multidrug resistance-associated protein isoform 4 in rat choroid plexus. J Neurochem. 2010;115(1):200–8.

    Article  CAS  PubMed  Google Scholar 

  137. Flores K, Manautou JE, Renfro JL. Gender-specific expression of ATP-binding cassette (Abc) transporters and cytoprotective genes in mouse choroid plexus. Toxicology. 2017;386:84–92.

    Article  CAS  PubMed  Google Scholar 

  138. Strazielle N, Ghersi-Egea JF. Physiology of blood–brain interfaces in relation to brain disposition of small compounds and macromolecules. Mol Pharm. 2013;10(5):1473–91.

    Article  CAS  PubMed  Google Scholar 

  139. Strazielle N, Khuth ST, Ghersi-Egea J-F. Detoxification systems, passive and specific transport for drugs at the blood–CSF barrier in normal and pathological situations. Adv Drug Deliv Rev. 2004;56(12):1717–40.

    Article  CAS  PubMed  Google Scholar 

  140. Ghersi-Egea JF, Leninger-Muller B, Suleman G, Siest G, Minn A. Localization of drug-metabolizing enzyme activities to blood-brain interfaces and circumventricular organs. J Neurochem. 1994;62(3):1089–96.

    Article  CAS  PubMed  Google Scholar 

  141. Kratzer I, Liddelow SA, Saunders NR, Dziegielewska KM, Strazielle N, Ghersi-Egea J-F. Developmental changes in the transcriptome of the rat choroid plexus in relation to neuroprotection. Fluids Barriers CNS. 2013;10(1):25.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Granberg L, Östergren A, Brandt I, Brittebo EB. CYP1A1 and CYP1B1 in blood-brain interfaces: CYP1A1-dependent bioactivation of 7,12-dimethylbenz(a)anthracene in endothelial cells. Drug Metab Dispos. 2003;31(3):259–65.

    Article  CAS  PubMed  Google Scholar 

  143. Janmohamed A, Hernandez D, Phillips IR, Shephard EA. Cell-, tissue-, sex- and developmental stage-specific expression of mouse flavin-containing monooxygenases (Fmos). Biochem Pharmacol. 2004;68(1):73–83.

    Article  CAS  PubMed  Google Scholar 

  144. Lindvall M, Hardebo JE, Owman CH. Barrier mechanisms for neurotransmitter monoamines in the choroid plexus. Acta Physiol Scand. 1980;108(3):215–21.

    Article  CAS  PubMed  Google Scholar 

  145. Vitalis T, Fouquet C, Alvarez C, Seif I, Price D, Gaspar P, et al. Developmental expression of monoamine oxidases A and B in the central and peripheral nervous systems of the mouse. J Comp Neurol. 2002;442(4):331–47.

    Article  CAS  PubMed  Google Scholar 

  146. Gong B, Boor PJ. The role of amine oxidases in xenobiotic metabolism. Expert Opin Drug Metab Toxicol. 2006;2(4):559–71.

    Article  CAS  PubMed  Google Scholar 

  147. Ghersi-Egea J-F, Strazielle N, Murat A, Jouvet A, Buénerd A, Belin M-F. Brain protection at the blood–cerebrospinal fluid interface involves a glutathione-dependent metabolic barrier mechanism. J Cereb Blood Flow Metab. 2006;26(9):1165–75.

    Article  CAS  PubMed  Google Scholar 

  148. Kratzer I, Strazielle N, Saudrais E, Mönkkönen K, Malleval C, Blondel S, et al. Glutathione conjugation at the blood–CSF barrier efficiently prevents exposure of the developing brain fluid environment to blood-borne reactive electrophilic substances. J Neurosci. 2018;38(14):3466–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Leininger-Muller B, Ghersi-Egea JF, Siest G, Minn A. Induction and immunological characterization of the uridine diphosphate-glucuronosyltransferase conjugating 1-naphthol in the rat choroid plexus. Neurosci Lett. 1994;175(1–2):37–40.

    Article  CAS  PubMed  Google Scholar 

  150. Martinasevic MK, King CD, Rios GR, Tephly TR. Immunohistochemical localization of UDP-glucuronosyltransferases in rat brain during early development. Drug Metab Dispos. 1998;26(10):1039–41.

    CAS  PubMed  Google Scholar 

  151. James MO, Ambadapadi S. Interactions of cytosolic sulfotransferases with xenobiotics. Drug Metab Rev. 2013;45(4):401–14.

    Article  CAS  PubMed  Google Scholar 

  152. Richard K, Hume R, Kaptein E, Stanley EL, Visser TJ, Coughtrie MW. Sulfation of thyroid hormone and dopamine during human development: ontogeny of phenol sulfotransferases and arylsulfatase in liver, lung, and brain. J Clin Endocrinol Metab. 2001;86(6):2734–42.

    CAS  PubMed  Google Scholar 

  153. Hammarlund-Udenaes M. Microdialysis in CNS PKPD research: unraveling unbound concentrations BT - microdialysis in drug development. In: Müller M, editor. . New York: Springer New York; 2013. p. 83–102.

    Google Scholar 

  154. Watson J, Wright S, Lucas A, Clarke KL, Viggers J, Cheetham S, et al. Receptor occupancy and brain free fraction. Drug Metab Dispos. 2009;37(4):753–60.

    Article  CAS  PubMed  Google Scholar 

  155. Lin JH. CSF as a surrogate for assessing CNS exposure: an industrial perspective. Curr Drug Metab. 2008;9(1):46–59.

    Article  CAS  PubMed  Google Scholar 

  156. Hammarlund-Udenaes M. Active-site concentrations of chemicals – are they a better predictor of effect than plasma/organ/tissue concentrations? Basic Clin Pharmacol Toxicol. 2010;106(3):215–20.

    Article  CAS  PubMed  Google Scholar 

  157. Liu X, Smith BJ, Chen C, Callegari E, Becker SL, Chen X, et al. Evaluation of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration. Drug Metab Dispos. 2006;34(9):1443–7.

    Article  CAS  PubMed  Google Scholar 

  158. Nagaya Y, Katayama K, Kusuhara H, Nozaki Y. Impact of P-glycoprotein–mediated active efflux on drug distribution into lumbar cerebrospinal fluid in nonhuman primates. Drug Metab Dispos. 2020;48(11):1183–90.

    Article  CAS  PubMed  Google Scholar 

  159. Yaguchi Y, Tachikawa M, Zhang Z, Terasaki T. Organic anion-transporting polypeptide 1a4 (Oatp1a4/Slco1a4) at the blood–arachnoid barrier is the major pathway of sulforhodamine-101 clearance from cerebrospinal fluid of rats. Mol Pharm. 2019;4:acs.molpharmaceut.9b00005.

    Google Scholar 

  160. Syková E, Nicholson C. Diffusion in Brain Extracellular Space. Physiol Rev. 2008;88(4):1277–340.

    Article  PubMed  Google Scholar 

  161. Pizzo ME, Wolak DJ, Kumar NN, Brunette E, Brunnquell CL, Hannocks M-J, et al. Intrathecal antibody distribution in the rat brain: surface diffusion, perivascular transport and osmotic enhancement of delivery. J Physiol. 2018;596(3):445–75.

    Article  CAS  PubMed  Google Scholar 

  162. Chang H-Y, Wu S, Meno-Tetang G, Shah DK. A translational platform PBPK model for antibody disposition in the brain. J Pharmacokinet Pharmacodyn. 2019;46(4):319–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported in part by NIH grants R01 GM066233 and funding from the Elmer M. Plein Endowment Research Fund.

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    Austin Sun & Joanne Wang

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Sun, A., Wang, J. Choroid Plexus and Drug Removal Mechanisms. AAPS J 23, 61 (2021). https://doi.org/10.1208/s12248-021-00587-9

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