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Distribution: Across Barriers

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Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

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Abstract

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 chapter “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 (section “Blood–Brain Barrier (BBB)”). They cover primary cultures of brain endothelial cells in monoculture or as coculture with astrocytes or pericytes (section “Primary Cultures of Brain Capillary Endothelial Cells”), immortalized endothelial cell lines from different species (section “Cocultures of Bovine Brain Microvascular Endothelial Cells and Rat Astrocytes”), and surrogate models (section “A Surrogate BBB Model: MDCK-MDR1 Cells”).

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References and Further Reading

  • 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 326:983–990

    Article  CAS  Google Scholar 

  • Abott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37:13–25

    Article  Google Scholar 

  • 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 17:1414–1421

    Article  CAS  Google Scholar 

  • 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 273:32167–32175

    Article  CAS  Google Scholar 

  • 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 57:760–768

    Article  CAS  Google Scholar 

  • 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 67:988–995

    Article  CAS  Google Scholar 

  • 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 333:193–196

    Article  CAS  Google Scholar 

  • 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 107:255–265

    Article  CAS  Google Scholar 

  • Bornstein MB (1958) Reconstituted rattail collagen used as substrate for tissue cultures on coverslips in maximow slides and roller tubes. Lab Investig 7:134–137

    CAS  Google Scholar 

  • 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 18:626–632

    Article  CAS  Google Scholar 

  • 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 14:396–402

    Article  CAS  Google Scholar 

  • Boyer JL, Meier PJ (1990) Characterizing mechanisms of hepatic bile acid transport utilizing isolated membrane vesicles. Methods Enzymol 192:517–533

    Article  CAS  Google Scholar 

  • Brewer CB (1994) Cytomegalovirus plasmid vectors for permanent lines of polarized epithelial cells. Methods Cell Biol 43(Pt A):233–245

    Article  CAS  Google Scholar 

  • Buchler M, Bohme M, Ortlepp H, Keppler D (1994) Functional reconstitution of ATP-dependent transporters from the solubilized hepatocyte canalicular membrane. Eur J Biochem 224:345–352

    Article  CAS  Google Scholar 

  • 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 271:15091–15098

    Article  CAS  Google Scholar 

  • 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 81:1–8

    Article  Google Scholar 

  • 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 36:165–178

    Article  CAS  Google Scholar 

  • 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 37:380–385

    Article  CAS  Google Scholar 

  • 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 62:151–163

    Article  CAS  Google Scholar 

  • 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 281:304–314

    CAS  Google Scholar 

  • 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):156–164

    Article  CAS  Google Scholar 

  • 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 271–301

    Google Scholar 

  • 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 55:929–937

    CAS  Google Scholar 

  • 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 276:9626–9630

    Article  CAS  Google Scholar 

  • 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 60:934–943

    Article  CAS  Google Scholar 

  • 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 43:297–307

    Article  Google Scholar 

  • 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 54:1798–1801

    Article  CAS  Google Scholar 

  • 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 126:465–473

    Article  CAS  Google Scholar 

  • 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 88:23–31

    Article  CAS  Google Scholar 

  • Eisenblatter T, Galla HJ (2002) A new multidrug resistance protein at the blood-brain barrier. Biochem Biophys Res Commun 293:1273–1278

    Article  Google Scholar 

  • 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 York

    Google Scholar 

  • 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 971:221–231

    Article  CAS  Google Scholar 

  • 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 419:112–116

    Article  CAS  Google Scholar 

  • 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 818:65–71

    Article  CAS  Google Scholar 

  • 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 5:248–256

    Article  CAS  Google Scholar 

  • Gerhart DZ, Broderius MA, Drewes LR (1988) Cultured human and canine endothelial cells from brain microvessels. Brain Res Bull 21:785–793

    Article  CAS  Google Scholar 

  • 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 93:957–968

    Article  CAS  Google Scholar 

  • 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 127:121–136

    Article  CAS  Google Scholar 

  • Graham FL, van der Eb AJ (1973) A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology 52:456–467

    Article  CAS  Google Scholar 

  • 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 71:51–63

    Article  CAS  Google Scholar 

  • Hagenbuch B, Lubbert H, Stieger B, Meier PJ (1990) Expression of the hepatocyte Na+/bile acid cotransporter in Xenopus laevis oocytes. J Biol Chem 265:5357–5360

    Article  CAS  Google Scholar 

  • Hagos Y, Bahn A, Vormfelde SV, Brockmoller J, Burckhardt G (2007) Torasemide transport by organic anion transporters contributes to hyperuricemia. J Am Soc Nephrol 18:3101–3109

    Article  CAS  Google Scholar 

  • 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 247:312–315

    Article  CAS  Google Scholar 

  • 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 31:447–451

    Article  CAS  Google Scholar 

  • 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 274:37161–37168

    Article  CAS  Google Scholar 

  • 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 88:28–33

    Article  CAS  Google Scholar 

  • 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 54:4833–4836

    CAS  Google Scholar 

  • 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 56:988–994

    CAS  Google Scholar 

  • Keppler D, Jedlitschky G, Leier I (1998) Transport function and substrate specificity of multidrug resistance protein. Methods Enzymol 292:607–616

    Article  CAS  Google Scholar 

  • 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 163:546–555

    Article  CAS  Google Scholar 

  • Kopplow K, Letschert K, Konig J, Walter B, Keppler D (2005) Human hepatobiliary transport of organic anions analyzed by quadruple-transfected cells. Mol Pharmacol 68:1031–1038

    Article  CAS  Google Scholar 

  • 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 1165:228–239

    Article  Google Scholar 

  • 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 109:1274–1282

    Article  CAS  Google Scholar 

  • Lecluyse EL, Bullock PL, Parkinson A, Hochman JH (1996) Cultured rat hepatocytes. Pharm Biotechnol 8:121–159

    Article  CAS  Google Scholar 

  • 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 269:27807–27810

    Article  CAS  Google Scholar 

  • Leier I, Jedlitschky G, Buchholz U, Keppler D (1994b) Characterization of the ATP-dependent leukotriene C4 export carrier in mastocytoma cells. Eur J Biochem 220:599–606

    Article  CAS  Google Scholar 

  • Leier I, Hummel-Eisenbeiss J, Cui Y, Keppler D (2000) ATP-dependent para-aminohippurate transport by apical multidrug resistance protein MRP2. Kidney Int 57:1636–1642

    Article  CAS  Google Scholar 

  • Levin VA (1980) Relationship of octanol/water partition coefficient and molecular weight to rat brain capillary permeability. J Med Chem 23:682–684

    Article  CAS  Google Scholar 

  • Li AP (2010) Evaluation of drug metabolism, drug-drug interactions, and in vitro hepatotoxicity with cryopreserved human hepatocytes. Methods Mol Biol 640:281–294

    Article  CAS  Google Scholar 

  • 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 27:637–644

    CAS  Google Scholar 

  • 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 Phys 277:G12–G21

    CAS  Google Scholar 

  • Maeda K, Sugiyama Y (2010) The use of hepatocytes to investigate drug uptake transporters. Methods Mol Biol 640:327–353

    Article  CAS  Google Scholar 

  • 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 303:1029–1037

    Article  Google Scholar 

  • 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 53:1363–1371

    Article  CAS  Google Scholar 

  • Meyer SA, Ingraham CA, McCarthy KD (1989) Expression of vimentin by cultured astroglia and oligodendroglia. J Neurosci Res 24:251–259

    Article  CAS  Google Scholar 

  • 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 514:305–309

    Article  CAS  Google Scholar 

  • Mischeck U, Meyer J, Galla HJ (1989) Characterization of gamma-glutamyl transpeptidase activity of cultured endothelial cells from porcine brain capillaries. Cell Tissue Res 256:221–226

    Article  CAS  Google Scholar 

  • 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 267:433–437

    Article  CAS  Google Scholar 

  • 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 11:1187–1197

    Article  CAS  Google Scholar 

  • 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 27:687–694

    Article  CAS  Google Scholar 

  • 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 York

    Google Scholar 

  • 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 981:30–40

    Article  CAS  Google Scholar 

  • Ohno K, Pettigrew KD, Rapoport SI (1978) Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious Rat. Am J Phys 235:H299–H307

    CAS  Google Scholar 

  • 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 253:884–891

    CAS  Google Scholar 

  • 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 3:279–289

    Article  Google Scholar 

  • 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 299:620–628

    CAS  Google Scholar 

  • 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 71:705–715

    Article  CAS  Google Scholar 

  • 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 1540:233–242

    Article  CAS  Google Scholar 

  • Rose KA, Kostrubsky V, Sahi J (2006) Hepatobiliary disposition in primary cultures of dog and monkey hepatocytes. Mol Pharm 3:266–274

    Article  CAS  Google Scholar 

  • 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 48:437–447

    Article  CAS  Google Scholar 

  • 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 159:101–113

    Article  CAS  Google Scholar 

  • 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 24:984–989

    CAS  Google Scholar 

  • 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 267:4854–4858

    Article  CAS  Google Scholar 

  • 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 277:6497–6503

    Article  CAS  Google Scholar 

  • 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 76:894–903

    Article  CAS  Google Scholar 

  • 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 93:790–799

    CAS  Google Scholar 

  • 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 311:228–236

    Article  CAS  Google Scholar 

  • 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 169:455–467

    Article  CAS  Google Scholar 

  • 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 7:491–500

    Article  CAS  Google Scholar 

  • 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 91–97

    Google Scholar 

  • 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 1347:1–10

    Article  CAS  Google Scholar 

  • 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):1284–1293

    Article  CAS  Google Scholar 

  • Thanabalasundaram G, El-Gindi J, Lischper M, Galla HJ (2011b) Methods to assess pericyte-endothelial cell interactions in a coculture model. Methods Mol Biol 686:379–399

    Article  CAS  Google Scholar 

  • 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 66:579–587

    Article  CAS  Google Scholar 

  • 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 318:881–889

    Article  CAS  Google Scholar 

  • 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 71:1520–1529

    Article  CAS  Google Scholar 

  • 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 36:164–172

    Article  CAS  Google Scholar 

  • 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 437:925–934

    Article  CAS  Google Scholar 

  • 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 22:2497–2503

    Article  CAS  Google Scholar 

  • 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 25:1123–1129

    Google Scholar 

  • 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 76:47–53

    CAS  Google Scholar 

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Authors and Affiliations

  1. R&D Drug Metabolims and Pharmacokinetics, Sanofi Deutschland GmbH, Frankfurt am Main, Germany

    Tanja Eisenblaetter

  2. Department of Vegetative Physiology and Pathology, Georg-August University, Göttingen, Germany

    Yohannes Hagos

  3. PortaCellTec biosciences GmbH, Göttingen, Germany

    Saskia Flörl & Annett Kühne

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  1. Tanja Eisenblaetter
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  2. Yohannes Hagos
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Correspondence to Tanja Eisenblaetter .

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  1. FJH Safety Pharm Consulting, Dieburg, Hessen, Germany

    Franz J. Hock

  2. Cytokinetics (United States), South San Francisco, CA, USA

    Michael K. Pugsley

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  1. Toxicology, Cytokinetics, South San Francisco, CA, USA

    Michael K. Pugsley

  2. self employes, Dieburg, Deutschland

    Franz J. Hock DSc

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Eisenblaetter, T., Hagos, Y., Flörl, S., Kühne, A. (2022). Distribution: Across Barriers. In: Hock, F.J., Pugsley, M.K. (eds) Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Springer, Cham. https://doi.org/10.1007/978-3-030-73317-9_38-1

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  • DOI: https://doi.org/10.1007/978-3-030-73317-9_38-1

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-73317-9

  • Online ISBN: 978-3-030-73317-9

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

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