The Absorption Barrier

  • Gerrit BorchardEmail author


This chapter attempts to give an overview on the properties of the intestinal epithelium with regard to both, barriers to transcellular (transporter and efflux systems) and paracellular (tight junctional complex) drug absorption and transport systems and tight junction modulation. A short introduction into the relation between the innate immune system and modulation of paracellular permeability is equally given.


Tight Junction Intestinal Epithelium Breast Cancer Resistance Protein Trefoil Family Factor Tight Junctional Complex 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abreu MT, Fukata M, Arditi M (2005) TLR signaling in the gut in health and disease. J Immunol 174:4453–4460PubMedGoogle Scholar
  2. Albert EJ, Marshall JS (2008) Aging in the absence of TLR2 is associated with reduced IFN-g responses in the large intestine and increased severity of induced colitis. J Leukoc Biol 3:833–842CrossRefGoogle Scholar
  3. Annaba F, Sarwar Z, Kumar P, Saksena S, Turner JR, Dudeja PK, Gill RK, Alrefai WA (2007) Modulation of ileal bile acid transporter (ASBT) activity by depletion of plasma membrane cholesterol: association with lipid rafts. Am J Physiol Gastrointest Liver Physiol 294:489–497CrossRefGoogle Scholar
  4. Balda MS, Garrett MD, Matter K (2003) The ZO-1-associated Y-box factor ZONAB regulates epithelial cell proliferation and cell density. J Cell Biol 160:423–432PubMedCrossRefGoogle Scholar
  5. Balimane PV, Sinko PJ (1999) Involvement of multiple transporters in the oral absorption of nucleoside analogues. Adv Drug Deliv Rev 39:183–209PubMedCrossRefGoogle Scholar
  6. Betanzos A, Huerta M, Lopez-Bayghen E, Azuara E, Amerena J, Gonzalez-Mariscal L (2004) The tight junction protein ZO-2 associates with Jun, Fos and C/EBP transcription factors in epithelial cells. Exp Cell Res 292:51–66PubMedCrossRefGoogle Scholar
  7. Boll M, Markovich D, Weber WM, Korte H, Daniel H, Murer H (1994) Expression cloning of a cDNA from rabbit small intestine related to proton-coupled transport of peptides, beta-lactam antibiotics and ACE-inhibitors. Plugers Arch 429:146–149CrossRefGoogle Scholar
  8. Borst P, Oude Elferink R (2002) Mammalian ABC transporters in health and disease. Annu Rev Biochem 71:537–592PubMedCrossRefGoogle Scholar
  9. Brodin B, Nielsen CU, Steffansen B, Frokjaer S (2002) Transport of peptidomimetic drugs by the intestinal di/tripeptide transporter, PepT1. Pharmacol Toxicol 90:285–296PubMedCrossRefGoogle Scholar
  10. Bry L, Falk P, Huttner K, Ouellette A, Midtvedt T, Gordon JI (1994) Paneth cell differentiation in the developing intestine of normal and transgenic mice. Proc Natl Acad Sci 91:10335–10339PubMedCrossRefGoogle Scholar
  11. Cario E, Gerken G, Podolsky DK (2007) Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterol 132:1359–1374CrossRefGoogle Scholar
  12. Chin AC, Vergnolle N, MacNaughton WK, Wallace JL, Hollenberg MD, Buret AG (2003) Proteinase-activated receptor 1 activation induces epithelial apoptosis and increases intestinal permeability. Proc Natl Acad Sci USA 100:11104–11109PubMedCrossRefGoogle Scholar
  13. Citi S (2001) The cytoplasmic plaque proteins of the tight junction. In: Anderson JM, Cereijido M (eds) Tight Junctions (2nd edn.): CRC, Boca Raton 2001, pp 231–264Google Scholar
  14. Clark DE (1999) Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena: 1. Prediction of intestinal absorption. J Pharm Sci 88:807–814PubMedCrossRefGoogle Scholar
  15. Clark DE, Grootenhuis PD (2003) Predicting passive transport in silico – history, hype, hope. Curr Top Med Chem 3:1193–1203PubMedCrossRefGoogle Scholar
  16. Conner SD, Schmid SL (2003) Regulated portals of entry into the cell. Nature 422:37–44PubMedCrossRefGoogle Scholar
  17. Daugherty AL, Mrsny RJ (1999) Transcellular uptake mechanisms of the intestinal epithelial barrier. Part one. PSTT 2:144–151Google Scholar
  18. Di Pierro M, Lu R, Uzzau S, Wang W, Margaretten K, Pazzani C, Maimone F, Fasano A (2001) Zonula occludens toxin structure-function analysis. J Biol Vhem 276:19160–19165CrossRefGoogle Scholar
  19. Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, Ross DD (1998) A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 95:15665–15670PubMedCrossRefGoogle Scholar
  20. Doyle LA, Ross DD (2003) Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 22:7340–7358PubMedCrossRefGoogle Scholar
  21. Dürr D, Stieger B, Kullak-Ublick GA, Rentsch KM, Steinert HC, Meier PJ, Fattinger K (2000) St. John’s Wort induces intestinal Pglycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin Pharmacol Ther 68:598–604.PubMedCrossRefGoogle Scholar
  22. El Asmar R, Panigrahi P, Bamford P, Berti I, Not T, Coppa GV, Catassi C, Fasano A (2002) Host-dependent zonulin secretion causes the impairment of the small intestin barrier function after bacterial exposure. Gastroenterol 123:1607–1615CrossRefGoogle Scholar
  23. Fanning AS, Anderson JM (1999) PDZ domains: fundamental building blocks in the organization of protein complexes at the plasma membrane. J Clin Invest 103:767–772PubMedCrossRefGoogle Scholar
  24. Fasano A, Baudry B, Pumplin DW, Wassermann SS, Tall BD, Ketley JM, Kaper JB (1991) Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions. Proc Natl Acad Sci USA 88:5242–5246PubMedCrossRefGoogle Scholar
  25. Fasano A, Fiorentini C, Donelli G, Uzzau S, Kaper JB, Margaretten K, Ding X, Guandalini S, Comstock L, Goldblum SE (1995) Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro. J Clin Investig 96:710–720PubMedCrossRefGoogle Scholar
  26. Fei YJ, Kanai Y, Nussberger S, Ganapathy V, Leibach FH, Romero MF, Singh SK, Boron WF, Hediger MA (1994) Expression cloning of a mammalian proton-coupled oligopeptide transporter. Nature 368:563–566PubMedCrossRefGoogle Scholar
  27. Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S (1993) Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 123:1777–1788PubMedCrossRefGoogle Scholar
  28. Furuse M, Fujimoto K, Sato N, Hirase T, Tsukita S, Tsukita S (1996) Overexpression of occludin, a tight junction-associated integral membrane protein, induces the formation of intracellular multilamellar bodies bearing tight junction-like structures. J Cell Sci 109:429–435PubMedGoogle Scholar
  29. Garcia-Gardena G, Oh P, Liu J, Schnitzer JE, Sessa WC (1996) Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling. Proc Natl Acad Sci USA 93:6448–6453CrossRefGoogle Scholar
  30. Halestrap AP, Price NT (1999) The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 343:281–299PubMedCrossRefGoogle Scholar
  31. Hamazaki Y, Itoh M, Sasaki H, Furuse M, Tsukita S (2002) Multi-PDZ domain protein 1 (MUPP1) is concentrated at tight junctions through its possible interaction with claudin-1 and junctional adhesion molecule. J Biol Chem 277:455–461PubMedCrossRefGoogle Scholar
  32. Han HK, Rie JK, Oh DM, Saito G, Hsu CP, Stewart BH, Amidon GL (1999) CHO/hPEPT1 cells overexpressing the human peptide transporter (hPEPT1) as an alternative in vitro model for peptidomimetic drugs. J Pharm Sci 88:347–350PubMedCrossRefGoogle Scholar
  33. Harder JL, Margolis B (2008) SnapShot: Tight and adherens junction signaling. Cell 133:1118PubMedCrossRefGoogle Scholar
  34. Hartsock A, Nelson WJ (2008) Adherens and tight junctions: Structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta 1778:660–669PubMedCrossRefGoogle Scholar
  35. Hirabayashi S, Tajima M, Yao I, Nishimura W, Mori H, Hata Y (2003) JAM-4, a junctional cell adhesion molecule interacting with a tight junction protein, MAGI-1. Mol Cell Biol 23:4267–4282,PubMedCrossRefGoogle Scholar
  36. Hoffmann W (2005) Trefoil factors TFF (trefoil factor family) peptide-triggered signals promoting mucosal restitution. Cell Mol Life Sci 62:2932–2938PubMedCrossRefGoogle Scholar
  37. Hommelgaard AM, Roepstorff K, Vilhardt F, Torgersen ML, Sandvig K, van Deurs B (2005) Caveolae: stable membrane domains with a potential for internalization. Traffic 6:720–724PubMedCrossRefGoogle Scholar
  38. Hu M, Subramanian P, Mosberg HI, Amidon GL (1989) Use of the peptide carrier system to improve the intestinal absorption of L-alpha-methydopa: carrier kinetics, intestinal permeabilities, and in vitro hydrolysis of dipeptidyl derivatives of L-alpha-methyldopa. Pharm Res 6:66–70PubMedCrossRefGoogle Scholar
  39. Itoh M, Furuse M, Morita K, Kubota K, Saitou M, Tsukita S (1999) Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2 and ZO-3, with the COOH termini of claudins. J Cell Biol 147:1351–1363PubMedCrossRefGoogle Scholar
  40. Jansen PL, van Klinken JW, van Gelder M, Ottenhoff R, Elferink RP (1993) Preserved organic anion transport in mutant TR-rats with a hepatobiliary secretion defect. Am J Physiol 265:G445–G452.PubMedGoogle Scholar
  41. Johanson K, Stintzing G, Magnusson KE, Sundqvist T, Jalil F, Murtaza A, Khan SR, Lindblad BS, Mollby R, Orusil E, Svensson L (1989) Intestinal permeability assessed with poly-ethylene glycols in children with diarrhea due to rotavirus and common bacterial pathogens in a developing community. J Pediatr Gastroenterol Nutr 9:307–313CrossRefGoogle Scholar
  42. Kipp H, Khoursandi S, Scharlau D, Kinne RKH (2003) More than apical: distribution of SLGT1 in Caco-2 cells. Am J Physiol Cell Physiol 54:C737–C749Google Scholar
  43. Kraehenbuhl J-P, Neutra MR (2000) Epithelial M cells: differentiation and function. Annu Rev Cell Dev Biol 16:301–332PubMedCrossRefGoogle Scholar
  44. Laura RP, Ross S, Koeppen H, Lasky LA (2002) MAGI-1: A widely expressed, alternatively spliced tight junction protein. Exp Cell Res 275:155–170PubMedCrossRefGoogle Scholar
  45. Leung S-M, Ruiz WG, Apodaca G (2000) Sorting of membrane and fluid at the apical pole of polarized MDCK cells. Mol Biol Cell 11:2131–2150PubMedGoogle Scholar
  46. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Del Rev 23:3–25CrossRefGoogle Scholar
  47. Mankertz J, Tavalali S, Schmitz H, Mankertz A, Riecken EO, Fromm M, Schulzke JD (2000) Expression from the human occludin promoter is affected by tumor necrosis factor alpha and interferon gamma. J Cell Sci 113:2085–2090PubMedGoogle Scholar
  48. Marinaro M, Fasano A, De Magistris MT (2003) Zonula occludens toxin acts as an adjuvant through different mucosal routes and induces protective immune responses. Infect Immun 71:1897–1902PubMedCrossRefGoogle Scholar
  49. Martin-Padura I, Lostaglio S, Schneemann M, LW, Romano M, Fruscella P, Panzeri C, Stoppacciaro A, Ruco L, Villa A, Simmons D, Dejana E (1998) Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol 142:117–127Google Scholar
  50. Martinez-Estrada OM, Villa A, Breviario F, Orsenigro F, Dejana E, Bazzoni G (2001) Association of junctional adhesion molecule with calcium/calmodulin-dependent serine protein kinase (CASK/LIN-2) in human epithelial Caco-2 cells. J Biol Chem 276:9291–9296PubMedCrossRefGoogle Scholar
  51. Meyer zum Büschenfelde D, Tauber R, Huber O (2006) TFF3-peptide increases transepithelial resistance in epithelial cells by modulating claudin-1 and -2 expression. Peptides 27:3383–3390PubMedCrossRefGoogle Scholar
  52. Mitic LL, van Itallie CM (2001) Occludin and claudins: transmembrane proteins of the tight junction. In: Cereijido M, Anderson JM (eds) Tight Junctions (2nd edn.). CRC, Boca Raton, pp 213–230Google Scholar
  53. Mizuno N, Niwa T, Yotsumoto Y, Sugiyama Y (2003) Impact of drug transporter studies on drug discovery and development. Pharmacol Rev 55:425–461PubMedCrossRefGoogle Scholar
  54. Mostov KE, Verges M, Altschuler Y (2000) Membrane traffic in polarized epithelial cells. Curr Opin Cell Biol 12:483–490PubMedCrossRefGoogle Scholar
  55. Oh P, Borgström P, Witkiewicz H, Li Y, Borgström BJ, Chrastina A, Iwata K, Zinn KR, BAldwin R, Testa JE, Schnitzer JE (2007) Live dynamic imaging of caveolae pumping targeted antibody rapidly and specifically across endothelium in the lung. Nature Biotechnol 25:327–337CrossRefGoogle Scholar
  56. Palade GE (1953) Fine structure of blood capillaries. J Appl Physiol 24:1424Google Scholar
  57. Parton RG, Richards AA (2003) Lipid rafts and caveolae as portals for endocytosis: new insights and common mechanisms. Traffic 4:724–738PubMedCrossRefGoogle Scholar
  58. Powell DW (1981) Barrier function of epithelia. Am J Physiol Gastrointest Liver Physiol 241:G275–G288Google Scholar
  59. Rietveld A, Simons K (1998) The differential miscibility of lipids as basis for the formation of functional membrane rafts. Biochim Biophys Acta 1376:467–479PubMedGoogle Scholar
  60. Saitou M, Furuse M, Saski H, Schulzke JK, Fromm M, Takano H, Noda T, Tsukita S (2000) Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol Biol Cell 11:4131–4142PubMedGoogle Scholar
  61. Sanderson IR, Walker WA (1993) Uptake and transport of macromolecules by the intestine: possible role in clinical disorder (An update). Gastroenterol 104:622–629Google Scholar
  62. Schneeberger EE, Lynch RD (2004) The tight junction: a multifunctional complex. Am J Physiol Cell Physiol 286:1213–1228CrossRefGoogle Scholar
  63. Schinkel AH, Jonker JW (2003) Mammalian drug efflux transporters of ATP binding cassette (ABC) family: an overview. Adv Drug Del Rev 55:3–29CrossRefGoogle Scholar
  64. Shimizu R, Sukegawa T, Tsuda Y, Itoh T (2008) Quantitative prediction of oral absorption of PEPT1 substrates based on in vitro uptake into Caco-2 cells. Int J Pharm 354:104–110PubMedCrossRefGoogle Scholar
  65. Siccardi D, Turnerb JR, Mrsny R (2005) Regulation of intestinal epithelial function: a link between opportunities for macromolecular drug delivery and inflammatory bowel disease. Adv Drug Deliv Rev 57:219–235PubMedCrossRefGoogle Scholar
  66. Simionescu N (1983) Cellular aspects of transcapillary exchange. Physiol Rev 63:1536–1579PubMedGoogle Scholar
  67. Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387:569–572PubMedCrossRefGoogle Scholar
  68. Snoeck V, Goddeeris B, Cox E (2005) The role of enterocytes in the intestinal barrier function and antigen uptake. Microbes Infect 7:997–1004PubMedCrossRefGoogle Scholar
  69. Sugiyama Y, Kato Y (1994) Pharmacokinetic aspects of peptide delivery and targeting: importance of receptor-mediated endocytosis. Drug Dev Ind Pharm 20:591–614CrossRefGoogle Scholar
  70. Takano M, Yumoto R, Murakami T (2006) Expression and function of efflux transporters in the intestine. Pharmacol Therap 109:137–161CrossRefGoogle Scholar
  71. Tang VW, Goodenough DA (2003) Paracellular ion channel at the tight junction. Biophys J 84:1660–1673PubMedCrossRefGoogle Scholar
  72. Thomas CM, Smart EJ (2008) Caveolae structure and function. J Cell Mol Med 12:796–809PubMedCrossRefGoogle Scholar
  73. Tsuji A (2002) Transporter-mediated drug interactions. Drug Metab Pharmacokinet 17:253–274PubMedCrossRefGoogle Scholar
  74. Uittenbogaard A, Ying Y, Smart EJ (1998) Characterization of a cytosolic heat-shock protein-caveolin chaperone complex. Involvement in cholesterol trafficking. J Biol Chem 273:6525–6532.PubMedCrossRefGoogle Scholar
  75. Vasselon T, Detmers PA (2002) Toll receptors: a central element in innate immune responses. Infect Immun 70:1033–1041PubMedCrossRefGoogle Scholar
  76. Wang E, Brown PS, Aroeti B, Chapin SJ, Mostov KE, Dunn KD (2000) Apical and basolateral endocytic pathways of MDCK cells meet in acidic common endosomes distinct from a nearly-neutral apical recycling endosome. Traffic 1:480–493PubMedCrossRefGoogle Scholar
  77. Wang W, Uzzau S, Goldblum SE, Fasano A (2000) Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci 113:4435–4440PubMedGoogle Scholar
  78. Watts T, Berti I, Sapone A, Gerarduzzi T, Not T, Zielke R, Fasano A (2005) Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. Proc Natl Acad Sci USA 102:2916–2921PubMedCrossRefGoogle Scholar
  79. Wessel MD, Jurs PC, Tolan JW, Muskal SM (1998) Prediction of human intestinal absorption of drug compounds from molecular structure. J Chem Inf Comput Sci 38:726–735PubMedCrossRefGoogle Scholar
  80. Yu AS, Enck AH, Lencer WI, Schneeberger EE (2003) Claudin-8 expression in Madin-Darby canine kidney cells augments the paracellular barrier to cation permeation. J Biol Chem 278:17350–17359PubMedCrossRefGoogle Scholar
  81. Zolotarevsky Y, Hecht G, Koutsouris A, Gonzalez DE, Quan C, Tom J, Mrsny RJ, Turner JR (2002) A membrane-permeant peptide that inhibits MLC kinase restores barrier function in in vitro models of intestinal disease. Gastroenterol 123:163–172CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Laboratory of Pharmaceutics and Biopharmaceutics, School of Pharmaceutical SciencesUniversity of GenevaGenevaSwitzerland

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