Distribution: Across Barriers

  • Tanja Eisenblaetter
  • Yohannes Hagos
  • Saskia Flörl
  • Annett Kühne
Reference work entry


Distribution of drugs across barriers plays a predominant role in the processes of absorption (A), distribution (D), and excretion (E) and is thus a major determinant of a drugs pharmacokinetic profile. The barrier at the site of absorption is in most cases built by the enterocytes of the small intestine (see Chap.  29 “Absorption: In Vivo Tests (Radiolabeled)”). Apart from lung, heart, muscle, and brain, the main target organs are kidney and liver which are also the major elimination pathways of drugs. Cell membranes of liver hepatocytes and kidney cells have to be passed in these cases. The brain plays a special role in the distribution of drugs because drugs normally should not enter the central nervous system to avoid severe adverse effects. It is, therefore, protected by the very tight blood–brain barrier. However, when the target is located in the brain, the drug needs to cross this barrier. Meanwhile, there exist several in vitro systems to study drug permeation across this special blood–brain barrier (Sect. 36.1). They cover primary cultures of brain endothelial cells in monoculture or as coculture with astrocytes or pericytes (Sect. 36.1.1), immortalized endothelial cell lines from different species (Sect. 36.1.2), and surrogate models (Sect. 36.1.3).


Madine Darby Canine Kidney Multidrug Resistance Protein Madine Darby Canine Kidney Cell Brain Capillary Endothelial Cell RBE4 Cell 
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.

References and Further Reading

  1. Abe K, Bridges AS, Yue W, Brouwer KL (2008) In vitro biliary clearance of angiotensin II receptor blockers and 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors in sandwich-cultured rat hepatocytes: comparison with in vivo biliary clearance. J Pharmacol Exp Ther 326:983–990PubMedCrossRefGoogle Scholar
  2. Abott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37:13–25CrossRefGoogle Scholar
  3. Bakhiya N, Stephani M, Bahn A, Ugele B, Seidel A, Burckhardt G, Glatt H (2006) Uptake of chemically reactive, DNA-damaging sulfuric acid esters into renal cells by human organic anion transporters. J Am Soc Nephrol 17:1414–1421PubMedCrossRefGoogle Scholar
  4. Bakos E, Evers R, Szakacs G, Tusnady GE, Welker E, Szabo K, de Haas M, van Deemter L, Borst P, Varadi A, Sarkadi B (1998) Functional multidrug resistance protein (MRP1) lacking the N-terminal transmembrane domain. J Biol Chem 273:32167–32175PubMedCrossRefGoogle Scholar
  5. Bakos E, Evers R, Sinko E, Varadi A, Borst P, Sarkadi B (2000) Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions. Mol Pharmacol 57:760–768PubMedGoogle Scholar
  6. Begley DJ, Lechardeur D, Chen ZD, Rollinson C, Bardoul M, Roux F, Scherman D, Abbott NJ (1996) Functional expression of P-glycoprotein in an immortalised cell line of rat brain endothelial cells, RBE4. J Neurochem 67:988–995PubMedCrossRefGoogle Scholar
  7. Bohme M, Buchler M, Muller M, Keppler D (1993) Differential inhibition by cyclosporins of primary-active ATP-dependent transporters in the hepatocyte canalicular membrane. FEBS Lett 333:193–196PubMedCrossRefGoogle Scholar
  8. Bohme M, Muller M, Leier I, Jedlitschky G, Keppler D (1994) Cholestasis caused by inhibition of the adenosine triphosphate-dependent bile salt transport in Rat liver. Gastroenterology 107:255–265PubMedGoogle Scholar
  9. Bornstein MB (1958) Reconstituted rattail collagen used as substrate for tissue cultures on coverslips in maximow slides and roller tubes. Lab Invest 7:134–137PubMedGoogle Scholar
  10. Bowman PD, Betz AL, Goldstein GW (1982) Primary culture of microvascular endothelial cells from bovine retina: selective growth using fibronectin coated substrate and plasma derived serum. In Vitro 18:626–632PubMedCrossRefGoogle Scholar
  11. Bowman PD, Ennis SR, Rarey KE, Betz AL, Goldstein GW (1983) Brain microvessel endothelial cells in tissue culture: a model for study of blood-brain barrier permeability. Ann Neurol 14:396–402PubMedCrossRefGoogle Scholar
  12. Boyer JL, Meier PJ (1990) Characterizing mechanisms of hepatic bile acid transport utilizing isolated membrane vesicles. Methods Enzymol 192:517–533PubMedCrossRefGoogle Scholar
  13. Brewer CB (1994) Cytomegalovirus plasmid vectors for permanent lines of polarized epithelial cells. Methods Cell Biol 43(Pt A):233–245PubMedCrossRefGoogle Scholar
  14. Buchler M, Bohme M, Ortlepp H, Keppler D (1994) Functional reconstitution of ATP-dependent transporters from the solubilized hepatocyte canalicular membrane. Eur J Biochem 224:345–352PubMedCrossRefGoogle Scholar
  15. Buchler M, Konig J, Brom M, Kartenbeck J, Spring H, Horie T, Keppler D (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 271:15091–15098PubMedCrossRefGoogle Scholar
  16. Cajero-Juarez M, Avila B, Ochoa A, Garrido-Guerrero E, Varela-Echavarria A, Martinez D, Clapp C (2002) Immortalization of bovine umbilical vein endothelial cells: a model for the study of vascular endothelium. Eur J Cell Biol 81:1–8PubMedCrossRefGoogle Scholar
  17. Cecchelli R, Dehouck B, Descamps L, Fenart L, Buee-Scherrer VV, Duhem C, Lundquist S, Rentfel M, Torpier G, Dehouck MP (1999) In vitro model for evaluating drug transport across the blood-brain barrier. Adv Drug Deliv Rev 36:165–178PubMedCrossRefGoogle Scholar
  18. Chandra P, Lecluyse EL, Brouwer KL (2001) Optimization of culture conditions for determining hepatobiliary disposition of taurocholate in sandwich-cultured rat hepatocytes. In Vitro Cell Dev Biol Anim 37:380–385PubMedGoogle Scholar
  19. Chat M, Bayol-Denizot C, Suleman G, Roux F, Minn A (1998) Drug metabolizing enzyme activities and superoxide formation in primary and immortalized rat brain endothelial cells. Life Sci 62:151–163PubMedCrossRefGoogle Scholar
  20. Chu XY, Kato Y, Niinuma K, Sudo KI, Hakusui H, Sugiyama Y (1997) Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J Pharmacol Exp Ther 281:304–314PubMedGoogle Scholar
  21. Chu X, Huskey SE, Braun MP, Sarkadi B, Evans DC, Evers R (2004) Transport of ethinylestradiol glucuronide and ethinylestradiol sulfate by the multidrug resistance proteins MRP1, MRP2, and MRP3. J Pharmacol Exp Ther 309(1):156–164PubMedCrossRefGoogle Scholar
  22. Colman A (1984) Translation of eukaryotic mRNA in Xenopus oocytes. In: Hames D, Higgins SJ (eds) Transcription and translation – a practical approach. IRL Press, Oxford, pp 271–301Google Scholar
  23. Cui Y, Konig J, Buchholz JK, Spring H, Leier I, Keppler D (1999) Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol Pharmacol 55:929–937PubMedGoogle Scholar
  24. Cui Y, Konig J, Leier I, Buchholz U, Keppler D (2001a) Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J Biol Chem 276:9626–9630PubMedCrossRefGoogle Scholar
  25. Cui Y, Konig J, Keppler D (2001b) Vectorial transport by double-transfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2. Mol Pharmacol 60:934–943PubMedGoogle Scholar
  26. De Bruyn T, Ye ZW, Peeters A, Sahi J, Baes M, Augustijns PF, Annaert PP (2011) Determination of OATP-, NTCP- and OCT-mediated substrate uptake activities in individual and pooled batches of cryopreserved human hepatocytes. Eur J Pharm Sci 43:297–307PubMedCrossRefGoogle Scholar
  27. Dehouck MP, Meresse S, Delorme P, Fruchart JC, Cecchelli R (1990) An easier, reproducible, and mass-production method to study the blood-brain barrier in vitro. J Neurochem 54:1798–1801PubMedCrossRefGoogle Scholar
  28. Dehouck B, Dehouck MP, Fruchart JC, Cecchelli R (1994) Upregulation of the low density lipoprotein receptor at the blood-brain barrier: intercommunications between brain capillary endothelial cells and astrocytes. J Cell Biol 126:465–473PubMedCrossRefGoogle Scholar
  29. Demeuse P, Fragner P, Leroy-Noury C, Mercier C, Payen L, Fardel O, Couraud PO, Roux F (2004) Puromycin selectively increases Mdr1a expression in immortalized rat brain endothelial cell lines. J Neurochem 88:23–31PubMedCrossRefGoogle Scholar
  30. Eisenblatter T, Galla HJ (2002) A new multidrug resistance protein at the blood-brain barrier. Biochem Biophys Res Commun 293:1273–1278PubMedCrossRefGoogle Scholar
  31. Eisenblatter T, Psathaki K, Nitz T, Galla HJ, Wegener J (2001) Cell culture media: selection and standardization. In: Kobiler D (ed) Blood-brain barrier. Academic/Plenum, New YorkGoogle Scholar
  32. Eisenblatter T, Huwel S, Galla HJ (2003) Characterisation of the brain multidrug resistance protein (BMDP/ABCG2/BCRP) expressed at the blood-brain barrier. Brain Res 971:221–231PubMedCrossRefGoogle Scholar
  33. Evers R, Cnubben NH, Wijnholds J, van Deemter L, van Bladeren PJ, Borst P (1997) Transport of glutathione prostaglandin a conjugates by the multidrug resistance protein 1. FEBS Lett 419:112–116PubMedCrossRefGoogle Scholar
  34. Franke H, Galla HJ, Beuckmann CT (1999) An improved Low-permeability in vitro-model of the blood-brain barrier: transport studies on retinoids, sucrose, haloperidol, caffeine and mannitol. Brain Res 818:65–71PubMedCrossRefGoogle Scholar
  35. Franke H, Galla H, Beuckmann CT (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 Brain Res Protoc 5:248–256PubMedCrossRefGoogle Scholar
  36. Gerhart DZ, Broderius MA, Drewes LR (1988) Cultured human and canine endothelial cells from brain microvessels. Brain Res Bull 21:785–793PubMedCrossRefGoogle Scholar
  37. Gombar VK, Polli JW, Humphreys JE, Wring SA, Serabjit-Singh CS (2004) Predicting P-glycoprotein substrates by a quantitative structure-activity relationship model. J Pharm Sci 93:957–968PubMedCrossRefGoogle Scholar
  38. Gospodarowicz D, Massoglia S, Cheng J, Fujii DK (1986) Effect of fibroblast growth factor and lipoproteins on the proliferation of endothelial cells derived from bovine adrenal cortex, brain cortex, and corpus luteum capillaries. J Cell Physiol 127:121–136PubMedCrossRefGoogle Scholar
  39. Graham FL, van der Eb AJ (1973) A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology 52:456–467PubMedCrossRefGoogle Scholar
  40. Greenwood J, Pryce G, Devine L, Male DK, dos Santos WL, Calder VL, Adamson P (1996) SV40 Large T immortalised cell lines of the Rat blood-brain and blood-retinal barriers retain their phenotypic and immunological characteristics. J Neuroimmunol 71:51–63PubMedCrossRefGoogle Scholar
  41. Hagenbuch B, Lubbert H, Stieger B, Meier PJ (1990) Expression of the hepatocyte Na+/bile acid cotransporter in Xenopus laevis oocytes. J Biol Chem 265:5357–5360PubMedGoogle Scholar
  42. Hagos Y, Bahn A, Vormfelde SV, Brockmoller J, Burckhardt G (2007) Torasemide transport by organic anion transporters contributes to hyperuricemia. J Am Soc Nephrol 18:3101–3109PubMedCrossRefGoogle Scholar
  43. Hoheisel D, Nitz T, Franke H, Wegener J, Hakvoort A, Tilling T, Galla HJ (1998) Hydrocortisone reinforces the blood-brain properties in a serum free cell culture system. Biochem Biophys Res Commun 247:312–315PubMedCrossRefGoogle Scholar
  44. Houle R, Raoul J, Levesque JF, Pang KS, Nicoll-Griffith DA, Silva JM (2003) Retention of transporter activities in cryopreserved, isolated Rat hepatocytes. Drug Metab Dispos 31:447–451PubMedCrossRefGoogle Scholar
  45. Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, Yang WP, Kirchgessner TG (1999) A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of Rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem 274:37161–37168PubMedCrossRefGoogle Scholar
  46. Irvine JD, Takahashi L, Lockhart K, Cheong J, Tolan JW, Selick HE, Grove JR (1999) MDCK (madin-darby canine kidney) cells: a tool for membrane permeability screening. J Pharm Sci 88:28–33PubMedCrossRefGoogle Scholar
  47. Jedlitschky G, Leier I, Buchholz U, Center M, Keppler D (1994) ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Res 54:4833–4836PubMedGoogle Scholar
  48. Jedlitschky G, Leier I, Buchholz U, Barnouin K, Kurz G, Keppler D (1996) Transport of glutathione, glucuronate, and sulfate conjugates by the MRP gene-encoded conjugate export pump. Cancer Res 56:988–994PubMedGoogle Scholar
  49. Keppler D, Jedlitschky G, Leier I (1998) Transport function and substrate specificity of multidrug resistance protein. Methods Enzymol 292:607–616PubMedCrossRefGoogle Scholar
  50. Konig J, Zolk O, Singer K, Hoffmann C, Fromm MF (2011) Double-transfected MDCK cells expressing human OCT1/MATE1 or OCT2/MATE1: determinants of uptake and transcellular translocation of organic cations. Br J Pharmacol 163:546–555PubMedCrossRefGoogle Scholar
  51. Kopplow K, Letschert K, Konig J, Walter B, Keppler D (2005) Human hepatobiliary transport of organic anions analyzed by quadruple-transfected cells. Mol Pharmacol 68:1031–1038PubMedCrossRefGoogle Scholar
  52. Kroll S, El-Gindi J, Thanabalasundaram G, Panpumthong P, Schrot S, Hartmann C, Galla HJ (2009) Control of the blood-brain barrier by glucocorticoids and the cells of the neurovascular unit. Ann N Y Acad Sci 1165:228–239PubMedCrossRefGoogle Scholar
  53. Kullak-Ublick GA, Hagenbuch B, Stieger B, Schteingart CD, Hofmann AF, Wolkoff AW, Meier PJ (1995) Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver. Gastroenterology 109:1274–1282PubMedCrossRefGoogle Scholar
  54. Lecluyse EL, Bullock PL, Parkinson A, Hochman JH (1996) Cultured rat hepatocytes. Pharm Biotechnol 8:121–159PubMedGoogle Scholar
  55. Leier I, Jedlitschky G, Buchholz U, Cole SP, Deeley RG, Keppler D (1994a) The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. J Biol Chem 269:27807–27810PubMedGoogle Scholar
  56. Leier I, Jedlitschky G, Buchholz U, Keppler D (1994b) Characterization of the ATP-dependent leukotriene C4 export carrier in mastocytoma cells. Eur J Biochem 220:599–606PubMedCrossRefGoogle Scholar
  57. Leier I, Hummel-Eisenbeiss J, Cui Y, Keppler D (2000) ATP-dependent para-aminohippurate transport by apical multidrug resistance protein MRP2. Kidney Int 57:1636–1642PubMedCrossRefGoogle Scholar
  58. Levin VA (1980) Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 23:682–684PubMedCrossRefGoogle Scholar
  59. Li AP (2010) Evaluation of drug metabolism, drug-drug interactions, and in vitro hepatotoxicity with cryopreserved human hepatocytes. Methods Mol Biol 640:281–294PubMedCrossRefGoogle Scholar
  60. Liu X, Chism JP, Lecluyse EL, Brouwer KR, Brouwer KL (1999a) Correlation of biliary excretion in sandwich-cultured rat hepatocytes and in vivo in rats. Drug Metab Dispos 27:637–644PubMedGoogle Scholar
  61. Liu X, Lecluyse EL, Brouwer KR, Gan LS, Lemasters JJ, Stieger B, Meier PJ, Brouwer KL (1999b) Biliary excretion in primary rat hepatocytes cultured in a collagen-sandwich configuration. Am J Physiol 277:G12–G21PubMedGoogle Scholar
  62. Maeda K, Sugiyama Y (2010) The use of hepatocytes to investigate drug uptake transporters. Methods Mol Biol 640:327–353PubMedCrossRefGoogle Scholar
  63. Mahar Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ, Adkison KK, Polli JW (2002) Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharmacol Exp Ther 303:1029–1037PubMedCrossRefGoogle Scholar
  64. Meresse S, Dehouck MP, Delorme P, Bensaid M, Tauber JP, Delbart C, Fruchart JC, Cecchelli R (1989) Bovine brain endothelial cells express tight junctions and monoamine oxidase activity in long-term culture. J Neurochem 53:1363–1371PubMedCrossRefGoogle Scholar
  65. Meyer SA, Ingraham CA, McCarthy KD (1989) Expression of vimentin by cultured astroglia and oligodendroglia. J Neurosci Res 24:251–259PubMedCrossRefGoogle Scholar
  66. Meyer J, Mischeck U, Veyhl M, Henzel K, Galla HJ (1990) Blood-brain barrier characteristic enzymatic properties in cultured brain capillary endothelial cells. Brain Res 514:305–309PubMedCrossRefGoogle Scholar
  67. Mischeck U, Meyer J, Galla HJ (1989) Characterization of gamma-glutamyl transpeptidase activity of cultured endothelial cells from porcine brain capillaries. Cell Tissue Res 256:221–226PubMedCrossRefGoogle Scholar
  68. Mroczkowska JE, Roux FS, Nalecz MJ, Nalecz KA (2000) Blood-brain barrier controls carnitine level in the brain: a study on a model system with RBE4 cells. Biochem Biophys Res Commun 267:433–437PubMedCrossRefGoogle Scholar
  69. Muruganandam A, Herx LM, Monette R, Durkin JP, Stanimirovic DB (1997) Development of immortalized human cerebromicrovascular endothelial cell line as an in vitro model of the human blood-brain barrier. FASEB J 11:1187–1197PubMedGoogle Scholar
  70. Nakagawa S, Deli MA, Nakao S, Honda M, Hayashi K, Nakaoke R et al (2007) Pericytes from brain microvessels strengthen the barrier integrity in primary cultures of rat brain endothelial cells. Cell Mol Neurobiol 27:687–694PubMedCrossRefGoogle Scholar
  71. Nitz T, Haselbach M, Galla HJ (2001) Recent advances in the development of cell culture models for the blood-brain- and blood-CSF-barrier. In: Kobiler D (ed) Blood-brain barrier. Academic/Plenum, New YorkGoogle Scholar
  72. Nitz T, Eisenblatter T, Psathaki K, Galla HJ (2003) Serum-derived factors weaken the barrier properties of cultured porcine brain capillary endothelial cells in vitro. Brain Res 981:30–40PubMedCrossRefGoogle Scholar
  73. Ohno K, Pettigrew KD, Rapoport SI (1978) Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious Rat. Am J Physiol 235:H299–H307PubMedGoogle Scholar
  74. Pardridge WM, Triguero D, Yang J, Cancilla PA (1990) Comparison of in vitro and in vivo models of drug transcytosis through the blood-brain barrier. J Pharmacol Exp Ther 253:884–891PubMedGoogle Scholar
  75. Perriere N, Demeuse P, Garcia E, Regina A, Debray M, Andreux JP et al (2005) Puromycin-based purification of rat brain capillary endothelial cell cultures. Effect on the expression of blood-brain barrier-specific properties. J Neurochem 3:279–289CrossRefGoogle Scholar
  76. Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, Serabjit-Singh CS (2001) Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther 299:620–628PubMedGoogle Scholar
  77. Regina A, Koman A, Piciotti M, El Hafny B, Center MS, Bergmann R, Couraud PO, Roux F (1998) Mrp1 Multidrug resistance-associated protein and P-glycoprotein expression in rat brain microvessel endothelial cells. J Neurochem 71:705–715PubMedCrossRefGoogle Scholar
  78. Regina A, Morchoisne S, Borson ND, McCall AL, Drewes LR, Roux F (2001) Factor(s) released by glucose-deprived astrocytes enhance glucose transporter expression and activity in rat brain endothelial cells. Biochim Biophys Acta 1540:233–242PubMedCrossRefGoogle Scholar
  79. Rose KA, Kostrubsky V, Sahi J (2006) Hepatobiliary disposition in primary cultures of dog and monkey hepatocytes. Mol Pharm 3:266–274PubMedCrossRefGoogle Scholar
  80. Roux FS, Mokni R, Hughes CC, Clouet PM, Lefauconnier JM, Bourre JM (1989) Lipid synthesis by rat brain microvessel endothelial cells in tissue culture. J Neuropathol Exp Neurol 48:437–447PubMedCrossRefGoogle Scholar
  81. Roux F, Durieu-Trautmann O, Chaverot N, Claire M, Mailly P, Bourre JM, Strosberg AD, Couraud PO (1994) Regulation of gamma-glutamyl transpeptidase and alkaline phosphatase activities in immortalized rat brain microvessel endothelial cells. J Cell Physiol 159:101–113PubMedCrossRefGoogle Scholar
  82. Sallustio BC, Fairchild BA, Shanahan K, Evans AM, Nation RL (1996) Disposition of gemfibrozil and gemfibrozil acyl glucuronide in the rat isolated perfused liver. Drug Metab Dispos 24:984–989PubMedGoogle Scholar
  83. Sarkadi B, Price EM, Boucher RC, Germann UA, Scarborough GA (1992) Expression of the human multidrug resistance CDNA in insect cells generates a high activity drug-stimulated membrane ATPase. J Biol Chem 267:4854–4858PubMedGoogle Scholar
  84. Sasaki M, Suzuki H, Ito K, Abe T, Sugiyama Y (2002) Transcellular transport of organic anions across a double-transfected madin-darby canine kidney II cell monolayer expressing both human organic anion-transporting polypeptide (OATP2/SLC21A6) and multidrug resistance-associated protein 2 (MRP2/ABCC2). J Biol Chem 277:6497–6503PubMedCrossRefGoogle Scholar
  85. Sato T, Masuda S, Yonezawa A, Tanihara Y, Katsura T, Inui K (2008) Transcellular transport of organic cations in double-transfected MDCK cells expressing human organic cation transporters HOCT1/HMATE1 and HOCT2/HMATE1. Biochem Pharmacol 76:894–903PubMedCrossRefGoogle Scholar
  86. Scharschmidt BF, Keeffe EB, Blankenship NM, Ockner RK (1979) Validation of a recording spectrophotometric method for measurement of membrane-associated Mg- and NaK-ATPase activity. J Lab Clin Med 93:790–799PubMedGoogle Scholar
  87. Shitara Y, Hirano M, Sato H, Sugiyama Y (2004) Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil. J Pharmacol Exp Ther 311:228–236PubMedCrossRefGoogle Scholar
  88. Stanimirovic D, Morley P, Ball R, Hamel E, Mealing G, Durkin JP (1996) Angiotensin II-induced fluid phase endocytosis in human cerebromicrovascular endothelial cells is regulated by the inositol-phosphate signaling pathway. J Cell Physiol 169:455–467PubMedCrossRefGoogle Scholar
  89. Swift B, Brouwer KL (2010) Influence of seeding density and extracellular matrix on bile acid transport and Mrp4 expression in sandwich-cultured mouse hepatocytes. Mol Pharm 7:491–500PubMedCrossRefGoogle Scholar
  90. Tewes BJ, Franke H, Hellwig S, Hoheisel D, Decker S, Griesche D, Tilling T, Wegener J, Galla HJ (1997) Preparation of endothelial cells in primary cultures obtained from 6-month old pigs. In: de Boer AG, Sutanto W (eds) Transport across the blood-brain barrier: in vitro and in vivo techniques, Brain research pro. Harwood Academic, Amsterdam, pp 91–97Google Scholar
  91. Thanabalasundaram G, Pieper C, Lischper M, Galla HJ (2010) Regulation of the blood-brain barrier integrity by pericytes via matrix metalloproteinases mediated activation of vascular endothelial growth factor in vitro. Brain Res 1347:1–10PubMedCrossRefGoogle Scholar
  92. Thanabalasundaram G, Schneidewind J, Pieper C, Galla HJ (2011a) The impact of pericytes on the blood-brain barrier integrity depends critically on the pericyte differentiation stage. Int J Biochem Cell Biol 43(9):1284–1293PubMedCrossRefGoogle Scholar
  93. Thanabalasundaram G, El-Gindi J, Lischper M, Galla HJ (2011b) Methods to assess pericyte-endothelial cell interactions in a coculture model. Methods Mol Biol 686:379–399PubMedCrossRefGoogle Scholar
  94. Theron D, de Lagerie SB, Tardivel S, Pelerin H, Demeuse P, Mercier C, Mabondzo A, Farinotti R, Lacour B, Roux F, Gimenez F (2003) Influence of tumor necrosis factor-alpha on the expression and function of P-glycoprotein in an immortalised rat brain capillary endothelial cell line, GPNT. Biochem Pharmacol 66:579–587PubMedCrossRefGoogle Scholar
  95. Turncliff RZ, Hoffmaster KA, Kalvass JC, Pollack GM, Brouwer KL (2006a) Hepatobiliary disposition of a drug/metabolite pair: comprehensive pharmacokinetic modeling in sandwich-cultured rat hepatocytes. J Pharmacol Exp Ther 318:881–889PubMedCrossRefGoogle Scholar
  96. Turncliff RZ, Tian X, Brouwer KL (2006b) Effect of culture conditions on the expression and function of bsep, Mrp2, and Mdr1a/b in sandwich-cultured rat hepatocytes. Biochem Pharmacol 71:1520–1529PubMedCrossRefGoogle Scholar
  97. Vavricka SR, Van Montfoort J, Ha HR, Meier PJ, Fattinger K (2002) Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology 36:164–172PubMedCrossRefGoogle Scholar
  98. Wegener J, Zink S, Rosen P, Galla H (1999) Use of electrochemical impedance measurements to monitor beta-adrenergic stimulation of bovine aortic endothelial cells. Pflugers Arch 437:925–934PubMedCrossRefGoogle Scholar
  99. Wolff NA, Burckhardt BC, Burckhardt G, Oellerich M, Armstrong VW (2007) Mycophenolic acid (MPA) and its glucuronide metabolites interact with transport systems responsible for excretion of organic anions in the basolateral membrane of the human kidney. Nephrol Dial Transplant 22:2497–2503PubMedCrossRefGoogle Scholar
  100. Yamazaki M, Akiyama S, Ni’inuma K, Nishigaki R, Sugiyama Y (1997) Biliary excretion of pravastatin in rats: contribution of the excretion pathway mediated by canalicular multispecific organic anion transporter. Drug Metab Dispos 25:1123–1129PubMedGoogle Scholar
  101. Zhang W, Smith C, Monette R, Hutchison J, Stanimirovic DB (2000) Indomethacin and cyclosporin a inhibit in vitro ischemia-induced expression of ICAM-1 and chemokines in human brain endothelial cells. Acta Neurochir Suppl 76:47–53PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Tanja Eisenblaetter
    • 1
  • Yohannes Hagos
    • 2
  • Saskia Flörl
    • 3
  • Annett Kühne
    • 3
  1. 1.R&D Drug Metabolims and PharmacokineticsSanofi Deutschland GmbHFrankfurt am MainGermany
  2. 2.Department of Vegetative Physiology and PathologyGeorg-August UniversityGöttingenGermany
  3. 3.PortaCellTec biosciences GmbHGöttingenGermany

Personalised recommendations