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Passive Permeability And Active Transport Models For The Prediction Of Oral Absorption

P. Artursson, S. Neuhoff, S. Tavelin, P. Matsson
Published 2007 · Engineering

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A variety of cell culture models, including Caco-2 cells, are used to provide better pharmacokinetic decision grounds in drug discovery. This article examines the properties of such cell culture models and discusses their roles during the various stages in the drug discovery process. The strengths and weaknesses of different models for the assessment of passive drug permeability, active drug transport, and for the prediction of oral drug absorption are reviewed. The performance of the cell culture models as compared to emerging alternatives is also discussed. Further, the influence of the quality of the data and data sets used in permeability and transport assessment is investigated. We conclude that cell culture models can be used both as qualitative tools in higher-throughput modes and as quantitative tools for the selection of druglike compounds with optimal permeability and transport properties in later stages of the drug discovery process.
This paper references
10.1023/B:PHAM.0000008037.57884.11
Quantitative Biopharmaceutics Classification System: The Central Role of Dose/Solubility Ratio
E. Rinaki (2004)
10.1016/S0022-3468(98)90606-6
Glucose uptake in dilated small intestine.
A. Kawaguchi (1998)
10.1016/0378-5173(95)04204-0
Comparison between active and passive drug transport in human intestinal epithelial (Caco-2) cells in vitro and human jejunum in vivo
H. Lennernäs (1996)
10.1021/BI00434A042
The nature of the hydrophobic binding of small peptides at the bilayer interface: implications for the insertion of transbilayer helices.
R. Jacobs (1989)
10.1021/JM010253I
Physicochemical determinants of passive membrane permeability: role of solute hydrogen-bonding potential and volume.
J. T. Goodwin (2001)
10.1016/J.JPBA.2003.11.016
HPLC with programmed wavelength fluorescence detection for the simultaneous determination of marker compounds of integrity and P-gp functionality in the Caco-2 intestinal absorption model.
P. Augustijns (2004)
10.1007/BF00315491
Intraduodenal infusion of a water-based levodopa dispersion for optimisation of the therapeutic effect in severe Parkinson's disease
E. Bredberg (2004)
10.1111/J.1742-7843.2005.PTO960303.X
In silico predictions of drug solubility and permeability: two rate-limiting barriers to oral drug absorption.
C. Bergström (2005)
10.1016/0005-2736(92)90312-A
A new diffusion chamber system for the determination of drug permeability coefficients across the human intestinal epithelium that are independent of the unstirred water layer.
J. Karlsson (1992)
10.1016/S0006-8993(03)02401-6
Characterisation of the brain multidrug resistance protein (BMDP/ABCG2/BCRP) expressed at the blood–brain barrier
Tanja Eisenblaetter (2003)
10.1002/JPS.20206
Contribution of the paracellular route to the pH-dependent epithelial permeability to cationic drugs.
Naoki Nagahara (2004)
10.1007/PL00000912
From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance
T. Litman (2001)
10.1161/01.CIR.99.4.552
Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine [seecomments].
M. Fromm (1999)
10.1002/(SICI)1097-0029(20000515)49:4<394::AID-JEMT8>3.0.CO;2-K
Human cell models to study small intestinal functions: Recapitulation of the crypt‐villus axis
L. Pageot (2000)
10.1023/A:1016220428705
Does Fluid Flow Across the Intestinal Mucosa Affect Quantitative Oral Drug Absorption? Is It Time for a Reevaluation?
H. Lennernäs (2004)
10.1073/PNAS.190274097
A biosensor assay for studying ligand-membrane receptor interactions: binding of antibodies and HIV-1 Env to chemokine receptors.
T. Hoffman (2000)
10.1007/BF02110329
Drug-stimulated ATPase activity of the human P-glycoprotein
G. A. Scarborough (1995)
10.1016/0016-5085(95)90193-0
Effect of changing intestinal flow rate on a measurement of intestinal permeability.
K. D. Fine (1995)
10.1074/JBC.M109081200
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)*
M. Sasaki (2002)
10.1124/JPET.104.065342
HIV Protease Inhibitors Are Inhibitors but Not Substrates of the Human Breast Cancer Resistance Protein (BCRP/ABCG2)
A. Gupta (2004)
10.1111/j.1365-2036.1989.tb00254.x
pH‐Profile and regional transit times of the normal gut measured by a radiotelemetry device
J. Fallingborg (1989)
10.1023/A:1016212804288
A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability
G. Amidon (2004)
10.1016/0016-5085(88)90678-6
Human intestinal goblet cells in monolayer culture: characterization of a mucus-secreting subclone derived from the HT29 colon adenocarcinoma cell line.
T. Phillips (1988)
10.1053/GAST.2000.18148
Permeability of the rat small intestinal epithelium along the villus-crypt axis: effects of glucose transport.
B. Fihn (2000)
10.1016/0092-8674(94)90212-7
Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs
A. Schinkel (1994)
10.1002/JPS.10099
Contributions of saturable active secretion, passive transcellular, and paracellular diffusion to the overall transport of furosemide across adenocarcinoma (Caco-2) cells.
S. Flanagan (2002)
10.1023/A:1018816122458
Prediction of Membrane Permeability to Peptides from Calculated Dynamic Molecular Surface Properties
P. Stenberg (2004)
10.1111/J.1399-3054.1954.TB07589.X
The Permeability of Nitella Cells to Non‐Eleetrolytes
R. Collander (1954)
10.1021/JM021012T
Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Dietmar Schwab (2003)
10.1038/nrd1470
Can the pharmaceutical industry reduce attrition rates?
I. Kola (2004)
10.1023/A:1026450326712
Mechanisms of Transport and Structure-Permeability Relationship of Sulfasalazine and Its Analogs in Caco-2 Cell Monolayers
E. Liang (2004)
10.1016/S0378-5173(03)00372-7
Caco-2 permeability, P-glycoprotein transport ratios and brain penetration of heterocyclic drugs.
F. Faassen (2003)
10.1023/A:1013378731183
In Vitro Intestinal Permeability of Factor Xa Inhibitors: Influence of Chemical Structure on Passive Transport and Susceptibility to Efflux
N. G. Schipper (2004)
10.1124/JPET.104.068775
Differential Multidrug Resistance-Associated Protein 1 through 6 Isoform Expression and Function in Human Intestinal Epithelial Caco-2 Cells
Hannah M Prime-Chapman (2004)
10.1023/A:1016024005429
Lipophilicity in Molecular Modeling
B. Testa (2004)
Rational use of in vitro P-glycoprotein assays in drug discovery.
J. Polli (2001)
10.1023/A:1025001131513
Novel Experimental Parameters to Quantify the Modulation of Absorptive and Secretory Transport of Compounds by P-Glycoprotein in Cell Culture Models of Intestinal Epithelium
M. Troutman (2004)
10.1023/A:1018974519984
Regulation of Paracellular Absorption of Cimetidine and 5-Aminosalicylate in Rat Intestine
S. Zhou (2004)
10.1016/S0928-0987(99)00032-9
Chitosans as absorption enhancers of poorly absorbable drugs. 3: Influence of mucus on absorption enhancement.
N. G. Schipper (1999)
Effect of molecular charge on intestinal epithelial drug transport: pH-dependent transport of cationic drugs.
K. Palm (1999)
10.1016/S0925-4439(97)00026-4
Structure-activity relationships of P-glycoprotein interacting drugs: kinetic characterization of their effects on ATPase activity.
T. Litman (1997)
10.1023/A:1022643802296
An Improved Cell Culture Model Based on 2/4/A1 Cell Monolayers for Studies of Intestinal Drug Transport: Characterization of Transport Routes
S. Tavelin (2004)
10.1136/GUT.37.1.159-A
Physiology of the Gastrointestinal Tract (3rd ed)
Ian Foracs (1995)
10.1074/JBC.270.23.13665
Characterization of a Mucin cDNA Clone Isolated from HT-29 Mucus-secreting Cells.
T. Lesuffleur (1995)
10.1023/B:PHAM.0000041450.25106.c8
Identification of Biowaivers Among Class II Drugs: Theoretical Justification and Practical Examples
E. Rinaki (2004)
Influence of P-glycoprotein on the transport and metabolism of indinavir in Caco-2 cells expressing cytochrome P-450 3A4.
J. Hochman (2000)
10.1007/s11095-004-9007-1
In Vitro and ex Vivo Intestinal Tissue Models to Measure Mucoadhesion of Poly (Methacrylate) and N-Trimethylated Chitosan Polymers
S. Keely (2004)
10.1016/S0928-0987(00)00164-0
Cell cultures as tools in biopharmacy.
A. Braun (2000)
10.1074/jbc.M203134200
Phospholipase C-γ Modulates Epithelial Tight Junction Permeability through Hyperphosphorylation of Tight Junction Proteins*
P. D. Ward (2002)
10.1016/0168-3659(92)90067-2
The relationship between peptide structure and transport across epithelial cell monolayers
P. S. Burton (1992)
10.1016/S1359-6446(04)03354-9
Cell culture-based models for intestinal permeability: a critique.
P. Balimane (2005)
10.1038/NM1186
The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk
J. Jonker (2005)
10.1023/A:1025032511040
pH-Dependent Bidirectional Transport of Weakly Basic Drugs Across Caco-2 Monolayers: Implications for Drug–Drug Interactions
Sibylle Neuhoff (2004)
10.1002/j.1460-2075.1986.tb04382.x
The function of tight junctions in maintaining differences in lipid composition between the apical and the basolateral cell surface domains of MDCK cells.
G. Meer (1986)
10.1021/JS9803205
MDCK (Madin-Darby canine kidney) cells: A tool for membrane permeability screening.
J. D. Irvine (1999)
10.1124/MOL.60.5.934
Vectorial transport by double-transfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2.
Y. Cui (2001)
10.1023/A:1018838121975
Automated Absorption Assessment Using Caco-2 Cells Cultured on Both Sides of Polycarbonate Membranes
P. Garberg (2004)
Transepithelial transport of drugs by the multidrug transporter in cultured Madin-Darby canine kidney cell epithelia.
M. Horio (1989)
10.1023/A:1011944602662
Modulation of the Tight Junctions of the Caco-2 Cell Monolayers by H2-antagonists
L. Gan (2004)
10.1023/A:1018836803254
Absorption Profiles for Polyethylene Glycols After Regional Jejunal Perfusion and Oral Load in Healthy Humans
J. Soderholm (2004)
10.1136/ard.2002.005249
Development of sulfasalazine resistance in human T cells induces expression of the multidrug resistance transporter ABCG2 (BCRP) and augmented production of TNFα
J. W. van der Heijden (2004)
10.1023/B:PHAM.0000008043.71001.43
Development of a 7-Day, 96-Well Caco-2 Permeability Assay with High-Throughput Direct UV Compound Analysis
J. Alsenz (2004)
10.1097/00007691-200002000-00029
Role of P-glycoprotein in drug disposition.
Y. Tanigawara (2000)
10.1021/MP0340136
Human organic anion-transporting polypeptide OATP-A (SLC21A3) acts in concert with P-glycoprotein and multidrug resistance protein 2 in the vectorial transport of Saquinavir in Hep G2 cells.
Yaming Su (2004)
10.1002/3527601473.CH4
Studies of membrane permeability and oral absorption 6: Caco-2 and emerging alternatives for prediction of intestinal drug transport: A general overview.
P. Artursson (2003)
10.1016/S0169-409X(98)00037-4
The effect of physical barriers and properties on the oral absorption of particulates.
Norris (1998)
10.2165/00003088-200443150-00004
Biowaivers for Oral Immediate-Release Products
F. Faassen (2004)
10.1023/A:1013358126640
Comparative Studies on in Vitro Methods for Evaluating in Vivo Function of MDR1 P-Glycoprotein
Y. Adachi (2004)
10.1016/0014-5793(94)01199-0
Expression of cytochrome P‐450 3A in HT29‐MTX cells and Caco‐2 clone TC7
V. Carrière (1994)
10.1021/JM010152K
Graphical model for estimating oral bioavailability of drugs in humans and other species from their Caco-2 permeability and in vitro liver enzyme metabolic stability rates.
A. K. Mandagere (2002)
10.1002/JPS.10409
Experimental demonstration of the unstirred water layer effect on drug transport in Caco-2 cells.
K. Naruhashi (2003)
10.1021/J100066A040
Simulation of Water Transport through a Lipid Membrane
Siewert-Jan Marrink (1994)
10.1021/JP952956F
Permeation Process of Small Molecules across Lipid Membranes Studied by Molecular Dynamics Simulations
S. Marrink (1996)
10.1021/JS960067D
How structural features influence the biomembrane permeability of peptides.
P. S. Burton (1996)
10.1201/9780203909478-11
Quantitative Approaches to Delineate Passive Transport Mechanisms in Cell Culture Monolayers
Norman F. H. Ho (1999)
10.1023/A:1016473601633
Biopharmaceutics Classification System: The Scientific Basis for Biowaiver Extensions
L. Yu (2004)
10.1385/1-59259-185-X:233
Applications of epithelial cell culture in studies of drug transport.
S. Tavelin (2002)
10.1016/S0378-5173(98)00331-7
Use of Caco-2 cells and LC/MS/MS to screen a peptide combinatorial library for permeable structures.
C. L. Stevenson (1999)
Midazolam metabolism by modified Caco-2 monolayers: effects of extracellular protein binding.
J. Fisher (1999)
10.1016/S0928-0987(00)00097-X
Specificity of doxorubicin versus rhodamine-123 in assessing P-glycoprotein functionality in the LLC-PK1, LLC-PK1:MDR1 and Caco-2 cell lines.
I. C. J. van der Sandt (2000)
10.1124/JPET.103.060194
Functional Characterization of pH-Sensitive Organic Anion Transporting Polypeptide OATP-B in Human
T. Nozawa (2004)
10.1186/1741-7015-2-16
Membrane transport of camptothecin: facilitation by human P-glycoprotein (ABCB1) and multidrug resistance protein 2 (ABCC2)
Anita K Lalloo (2004)
10.1124/MOL.64.6.1530
A new principle for tight junction modulation based on occludin peptides.
S. Tavelin (2003)
10.1021/JM049717D
Time-related differences in the physical property profiles of oral drugs.
P. Leeson (2004)
10.1124/JPET.104.082255
Mediation of Highly Concentrative Uptake of Pregabalin by L-Type Amino Acid Transport in Chinese Hamster Ovary and Caco-2 Cells
T. Su (2005)
10.1023/A:1012188625088
Polar Molecular Surface Properties Predict the Intestinal Absorption of Drugs in Humans
K. Palm (2004)
10.1016/S0016-5085(99)70132-0
Cellular and molecular mechanisms of dietary regulation on rat intestinal H+/Peptide transporter PepT1.
T. Shiraga (1999)
10.1021/ci010330i
Three-Dimensional Quantitative Structure-Permeability Relationship Analysis for a Series of Inhibitors of Rhinovirus Replication
S. Ekins (2001)
10.1053/GAST.2002.32992
H/dipeptide absorption across the human intestinal epithelium is controlled indirectly via a functional Na/H exchanger.
D. T. Thwaites (2002)
10.1021/JS960110X
HT29-MTX/Caco-2 cocultures as an in vitro model for the intestinal epithelium: in vitro-in vivo correlation with permeability data from rats and humans.
E. Walter (1996)
10.1023/A:1023282312757
MDR1 Genotype-Related Duodenal Absorption Rate of Digoxin in Healthy Japanese Subjects
Y. Morita (2004)
10.1023/A:1022699920043
Prediction of the Oral Absorption of Low-Permeability Drugs Using Small Intestine-Like 2/4/A1 Cell Monolayers
S. Tavelin (2004)
10.1023/A:1018905109971
A Drug Absorption Model Based on the Mucus Layer Producing Human Intestinal Goblet Cell Line HT29-H
A. Wikman (2004)
10.1016/S1359-6446(03)02649-7
Pharmaceutical profiling in drug discovery.
E. Kerns (2003)
10.1023/A:1020483911355
Comparison of Human Duodenum and Caco-2 Gene Expression Profiles for 12,000 Gene Sequences Tags and Correlation with Permeability of 26 Drugs
D. Sun (2004)
10.1016/S0928-0987(99)00041-X
Paracellular drug transport across intestinal epithelia: influence of charge and induced water flux.
J. Karlsson (1999)
10.5414/CPP39093
A comprehensive account on the role of efflux transporters in the gastrointestinal absorption of 13 commonly used substrate drugs in humans.
W. Chiou (2001)
10.1172/JCI118535
Basolateral localization and export activity of the human multidrug resistance-associated protein in polarized pig kidney cells.
R. Evers (1996)
High lipophilicity decreases drug transport across intestinal epithelial cells.
P. Wils (1994)
10.1021/JM040780C
Dipeptidomimetic ketomethylene isosteres as pro-moieties for drug transport via the human intestinal di-/tripeptide transporter hPEPT1: design, synthesis, stability, and biological investigations.
J. Våbenø (2004)
10.1093/JNCI/92.20.1651
Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan.
J. Jonker (2000)
10.1016/S1056-8719(00)00107-6
Drug-like properties and the causes of poor solubility and poor permeability.
C. Lipinski (2000)
10.1172/JCI119886
Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA.
R. Evers (1998)
Increased lipophilicity and subsequent cell partitioning decrease passive transcellular diffusion of novel, highly lipophilic antioxidants.
G. Sawada (1999)
10.1158/0008-5472.CAN-03-3884
Membrane Transporters and Channels
Y. Huang (2004)
10.1002/JPS.10518
A new system for the prediction of drug absorption using a pH-controlled Caco-2 model: evaluation of pH-dependent soluble drug absorption and pH-related changes in absorption.
X. He (2004)
10.1053/GAST.2002.32975
Novel genes and functional relationships in the adult mouse gastrointestinal tract identified by microarray analysis.
M. D. Bates (2002)
10.1067/mcp.2000.109156
Increased drug delivery to the brain by P‐glycoprotein inhibition
A. Sadeque (2000)
10.1021/JM980313T
Evaluation of dynamic polar molecular surface area as predictor of drug absorption: comparison with other computational and experimental predictors.
K. Palm (1998)
10.1021/JM0001626
Inhibitors of NF-kappaB and AP-1 gene expression: SAR studies on the pyrimidine portion of 2-chloro-4-trifluoromethylpyrimidine-5-[N-(3', 5'-bis(trifluoromethyl)phenyl)carboxamide].
M. Palanki (2000)
10.1093/JNCI/92.16.1295
A family of drug transporters: the multidrug resistance-associated proteins.
P. Borst (2000)
10.1172/JCI118673
Use of maltose hydrolysis measurements to characterize the interaction between the aqueous diffusion barrier and the epithelium in the rat jejunum.
M. Levitt (1996)
10.1023/A:1015040217741
Polar Molecular Surface as a Dominating Determinant for Oral Absorption and Brain Penetration of Drugs
J. Kelder (2004)
10.1007/BF01316488
Role of villous surface area in absorption science versus religion
A. Strocchi (2005)
10.1002/JPS.1119
Progress and limitations in the use of in vitro cell cultures to serve as a permeability screen for the blood-brain barrier.
M. Gumbleton (2001)
10.1002/JPS.1111
HT29-MTX and Caco-2/TC7 monolayers as predictive models for human intestinal absorption: role of the mucus layer.
C. Pontier (2001)
10.1021/JM001101A
Experimental and computational screening models for the prediction of intestinal drug absorption.
P. Stenberg (2001)
CYP3A-like cytochrome P450-mediated metabolism and polarized efflux of cyclosporin A in Caco-2 cells.
L. Gan (1996)
10.1002/JPS.20064
Summary workshop report: biopharmaceutics classification system--implementation challenges and extension opportunities.
J. Polli (2004)
10.1023/A:1025049014674
Efflux Ratio Cannot Assess P-Glycoprotein-Mediated Attenuation of Absorptive Transport: Asymmetric Effect of P-Glycoprotein on Absorptive and Secretory Transport Across Caco-2 Cell Monolayers
M. Troutman (2004)
10.1002/JPS.10265
Automated analysis of polyethylene glycol-induced inhibition of P-glycoprotein activity in vitro.
Erin D. Hugger (2003)
10.1053/GAST.1997.V113.PM9322515
Cell dynamics and differentiation of conditionally immortalized human intestinal epithelial cells.
A. Quaroni (1997)
10.1023/B:PHAM.0000045246.94064.ab
Effects of Extracts of Commonly Consumed Food Supplements and Food Fractions on the Permeability of Drugs Across Caco-2 Cell Monolayers
Leena A. Laitinen (2004)
10.1023/A:1011953906065
Transfected Rat cMOAT Is Functionally Expressed on the Apical Membrane in Madin-Darby Canine Kidney (MDCK) Cells
Setsuo Kinoshita (2004)
10.1111/J.1742-7843.2005.PTO960304.X
Which in vitro screens guide the prediction of oral absorption and volume of distribution
H. Waterbeemd (2005)
10.1023/B:PHAM.0000026434.82855.69
Predicting P-Glycoprotein Effects on Oral Absorption: Correlation of Transport in Caco-2 with Drug Pharmacokinetics in Wild-Type and mdr1a(-/-) Mice in Vivo
A. Collett (2004)
10.1007/s11095-004-9004-4
Predicting Drug Disposition via Application of BCS: Transport/Absorption/ Elimination Interplay and Development of a Biopharmaceutics Drug Disposition Classification System
C. Wu (2004)
10.1023/A:1012155124489
Intestinal Drug Absorption and Metabolism in Cell Cultures: Caco-2 and Beyond
P. Artursson (2004)
10.1073/PNAS.97.7.3473
Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.
S. Hoffmeyer (2000)
10.1067/mcp.2003.27
P‐glycoprotein‐mediated intestinal and biliary digoxin transport in humans
S. Drescher (2003)
10.1083/JCB.77.3.853
Polarized monolayers formed by epithelial cells on a permeable and translucent support
M. Cereijido (1978)
10.2174/1389200033489389
Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data.
L. Benet (2003)
10.1023/A:1016045820933
In Vitro Permeability Through Caco-2 Cells is not Quantitatively Predictive of in Vivo Absorption for Peptide-Like Drugs Absorbed via the Dipeptide Transporter System
S. Chong (2004)
10.1016/0006-291X(91)91647-U
Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells.
P. Artursson (1991)
10.1016/0168-3659(90)90118-D
Transport and permeability properties of human Caco-2 cells: An in vitro model of the intestinal epithelial cell barrier
G. Wilson (1990)
10.1128/AAC.36.11.2462
Modification of cefixime bioavailability by nifedipine in humans: involvement of the dipeptide carrier system.
C. Duverne (1992)
10.1136/gut.28.6.707
Mucosal surface pH of the large intestine of the rat and of normal and inflamed large intestine in man.
N. Mcneil (1987)
10.1007/PL00012496
Physicochemical profiling in drug research: a brief survey of the state-of-the-art of experimental techniques
A. Avdeef (2002)
10.1023/A:1015937605100
Caco-2 Cell Monolayers as a Model for Drug Transport Across the Intestinal Mucosa
A. Hilgers (2004)
10.1067/mcp.2000.107579
Oral bioavailability of digoxin is enhanced by talinolol: Evidence for involvement of intestinal P‐glycoprotein
K. Westphal (2000)
10.1021/AC034679B
Development of LC/MS/MS methods for cocktail dosed Caco-2 samples using atmospheric pressure photoionization and electrospray ionization.
Kati Hakala (2003)
10.1021/JM011132L
An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors.
J. Mckenna (2002)
10.1002/(SICI)1520-6017(200001)89:1<63::AID-JPS7>3.0.CO;2-6
Caco-2 versus Caco-2/HT29-MTX co-cultured cell lines: permeabilities via diffusion, inside- and outside-directed carrier-mediated transport.
C. Hilgendorf (2000)
10.1124/MOL.104.008375
A Novel Strategy for the Enhancement of Drug Absorption Using a Claudin Modulator
M. Kondoh (2005)
10.2165/00003088-200342010-00003
Role of P-Glycoprotein in Pharmacokinetics
J. Lin (2003)
10.1016/S0928-0987(03)00204-5
Exploring the quantitative relationship between the level of MDR1 transcript, protein and function using digoxin as a marker of MDR1-dependent drug efflux activity.
J. Taipalensuu (2004)
10.1097/00002826-200305000-00010
Optimizing Levodopa Pharmacokinetics: Intestinal Infusion Versus Oral Sustained-Release Tablets
D. Nyholm (2003)
10.1021/JS960503W
Diffusion of drugs in native and purified gastrointestinal mucus.
A. Larhed (1997)
10.1002/JPS.2600790604
Epithelial transport of drugs in cell culture. I: A model for studying the passive diffusion of drugs over intestinal absorptive (Caco-2) cells.
P. Artursson (1990)
10.1093/JNCI/59.1.221
One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice.
J. Fogh (1977)
10.1021/JM020001X
Structure-activity relationship for enhancement of paracellular permeability across Caco-2 cell monolayers by 3-alkylamido-2-alkoxypropylphosphocholines.
Hui Ouyang (2002)
10.1186/1741-7015-2-8
Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring
G. Englund (2004)
10.1016/S1461-5347(98)00097-2
Physical chemical properties of oral drug candidates in the discovery and exploratory development settings
W. Curatolo (1998)
10.1002/(SICI)1097-0231(20000331)14:6<523::AID-RCM906>3.0.CO;2-T
High-throughput caco-2 cell permeability screening by cassette dosing and sample pooling approaches using direct injection/on-line guard cartridge extraction/tandem mass spectrometry.
H. Bu (2000)
10.1023/A:1018903931777
Selective Paracellular Permeability in Two Models of Intestinal Absorption: Cultured Monolayers of Human Intestinal Epithelial Cells and Rat Intestinal Segments
P. Artursson (2004)
10.1083/JCB.136.2.399
A Synthetic Peptide Corresponding to the Extracellular Domain of Occludin Perturbs the Tight Junction Permeability Barrier
V. Wong (1997)
10.1016/S0016-5085(89)80072-1
Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability.
I. Hidalgo (1989)
10.1016/0378-5173(91)90067-X
A method for the determination of cellular permeability coefficients and aqueous boundary layer thickness in monolayers of intestinal epithelial caco 2 cells grown in permeable filter chambers
J. Karlsson (1991)
10.1021/JM0491851
A pharmacophore hypothesis for P-glycoprotein substrate recognition using GRIND-based 3D-QSAR.
Giovanni Cianchetta (2005)
10.1136/gut.19.8.735
Acid microclimate in coeliac and Crohn's disease: a model for folate malabsorption.
M. Lucas (1978)
10.1038/clpt.1981.209
Digoxin bioavailability during quinidine administration
W. D. Hager (1981)
10.1002/JPS.20278
Multiple pathways are involved in the oral absorption of BMS-262084, a tryptase inhibitor, in rats: role of paracellular transport, binding to trypsin, and P-glycoprotein efflux.
A. Kamath (2005)
10.1002/MC.2940130302
Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P‐glycoprotein: Implications for drug delivery and activity in cancer chemotherapy
V. Wacher (1995)
10.1021/JP035260S
Permeation of small molecules through a lipid bilayer: a computer simulation study
Daniele Bemporad and (2004)
The gastric secretion of drugs: a pH partition hypothesis.
P. A. Shore (1957)
10.1128/AAC.44.1.207-209.2000
Bioavailability of Aciclovir after Oral Administration of Aciclovir and Its Prodrug Valaciclovir to Patients with Leukopenia after Chemotherapy
H. Steingrimsdottir (2000)
10.1023/A:1012021315576
Effects of Peptide Structure on Transport Properties of Seven Thyrotropin Releasing Hormone (TRH) Analogues in a Human Intestinal Cell Line (Caco-2)
U. Werner (2004)
10.1124/MOL.104.005009
Analysis of ATP-Binding Cassette Transporter Expression in Drug-Selected Cell Lines by a Microarray Dedicated to Multidrug Resistances⃞
Jean-Philippe Annereau (2004)
10.1002/JPS.20149
Usefulness of a novel Caco-2 cell perfusion system. I. In vitro prediction of the absorption potential of passively diffused compounds.
C. Masungi (2004)
10.1023/A:1026107906191
In Vitro System to Evaluate Oral Absorption of Poorly Water-Soluble Drugs: Simultaneous Analysis on Dissolution and Permeation of Drugs
M. Kataoka (2004)
10.1021/JM049711O
Exploring the role of different drug transport routes in permeability screening.
P. Matsson (2005)
10.1016/S0928-0987(02)00005-2
The effect of amiloride on the in vivo effective permeability of amoxicillin in human jejunum: experience from a regional perfusion technique.
H. Lennernäs (2002)
10.1016/J.EJPB.2005.01.004
Delivery aspects of small peptides and substrates for peptide transporters.
B. Steffansen (2005)
10.1016/J.EJPS.2004.11.011
Caco-2 permeability of weakly basic drugs predicted with the Double-Sink PAMPA method
A. Avdeef (2005)
10.1007/s00280-004-0931-x
Single nucleotide polymorphisms modify the transporter activity of ABCG2
Kuniaki Morisaki (2004)
10.1016/j.ddtec.2004.11.007
Lead- and drug-like compounds: the rule-of-five revolution.
C. Lipinski (2004)
10.1023/A:1012197110917
Comparison of CYP3A Activities in a Subclone of Caco-2 Cells (TC7) and Human Intestine
S. D. Raeissi (2004)
10.1208/ps010203
Prediction of dissolution-absorption relationships from a continuous dissolution/Caco-2 system
M. Ginski (2008)
10.1038/clpt.1988.93
Comparative effects of verapamil and isradipine on steady‐state digoxin kinetics
S. Rodin (1988)
10.1021/BK-1995-0589.CH009
Simulations of Drug Diffusion in Biomembranes
T. Stouch (1995)
10.1002/JPS.2600841011
Passive diffusion of weak organic electrolytes across Caco-2 cell monolayers: uncoupling the contributions of hydrodynamic, transcellular, and paracellular barriers.
A. Adson (1995)
10.1073/PNAS.85.12.4486
A retrovirus carrying an MDR1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells.
I. Pastan (1988)
10.1021/JM031022+
Phe-Gly dipeptidomimetics designed for the di-/tripeptide transporters PEPT1 and PEPT2: synthesis and biological investigations.
J. Våbenø (2004)
10.1021/JM020986I
Absorption classification of oral drugs based on molecular surface properties.
C. Bergström (2003)
10.1146/ANNUREV.PHYSIOL.60.1.143
Regulation of the movement of solutes across tight junctions.
J. Madara (1998)
10.1021/JM970530E
Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes.
M. Kansy (1998)
10.1124/JPET.104.081224
Vectorial Transport of the Peptide CCK-8 by Double-Transfected MDCKII Cells Stably Expressing the Organic Anion Transporter OATP1B3 (OATP8) and the Export Pump ABCC2
K. Letschert (2005)
10.1016/S1359-6446(97)01099-4
Managing the drug discovery/development interface
T. Kennedy (1997)
10.1124/pr.55.3.1
Impact of Drug Transporter Studies on Drug Discovery and Development
Naomi Mizuno (2003)
10.1021/JS980474K
Saturable transport of H2-antagonists ranitidine and famotidine across Caco-2 cell monolayers.
K. Lee (1999)
10.1023/A:1016476220296
Human Dipeptide Transporter, hPEPTl, Stably Transfected into Chinese Hamster Ovary Cells
Kuang-Ming Y. Covitz (2004)
10.1002/JPS.2600831103
Quantitative approaches to delineate paracellular diffusion in cultured epithelial cell monolayers.
A. Adson (1994)
10.1016/S0005-2736(99)00167-4
The multidrug resistance protein family.
P. Borst (1999)
10.1023/A:1010974909998
Transport of Lipophilic Drug Molecules in a New Mucus-Secreting Cell Culture Model Based on HT29-MTX Cells
I. Behrens (2004)
10.1111/J.1365-2125.1988.TB03318.X
Pharmaceutical innovation by the seven UK-owned pharmaceutical companies (1964-1985).
R. A. Prentis (1988)
10.1016/0169-409X(91)90013-3
B) Mechanisms of peptide and protein absorption
H. Nellans (1991)
10.1021/JS970332A
Human intestinal permeability.
H. Lennernäs (1998)
10.1021/JM9810102
Correlation of human jejunal permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate data analysis approach.
S. Winiwarter (1998)
10.1016/J.EJPS.2004.04.009
PAMPA--a drug absorption in vitro model 11. Matching the in vivo unstirred water layer thickness by individual-well stirring in microtitre plates.
A. Avdeef (2004)
10.1021/JM001020E
High-throughput permeability pH profile and high-throughput alkane/water log P with artificial membranes.
F. Wohnsland (2001)
10.1016/J.EJPB.2003.10.016
Characterization of Caco-2 cell monolayer drug transport properties by cassette dosing using UV/fluorescence HPLC.
J. Palmgrén (2004)
10.1124/MOL.64.2.279
Carboxylesterase-mediated sensitization of human tumor cells to CPT-11 cannot override ABCG2-mediated drug resistance.
M. Wierdl (2003)
Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers.
J. Taipalensuu (2001)
10.1016/0378-5173(80)90140-4
Quantitative mechanistic studies in simultaneous fluid flow and intestinal absorption using steroids as model solutes
I. Komiya (1980)
10.1007/s004240000440
Permeability of the proximal and distal rat colon crypt and surface epithelium to hydrophilic molecules
Britt-Marie Fihn (2001)
10.1124/MOL.104.004713
Molecular Determinants of Substrate/Inhibitor Binding to the Human and Rabbit Renal Organic Cation Transporters hOCT2 and rbOCT2
Wendy M Suhre (2005)
10.1023/A:1026402410783
The Influence of Donor and Reservoir Additives on Caco-2 Permeability and Secretory Transport of HIV Protease Inhibitors and Other Lipophilic Compounds
B. Aungst (2004)
10.1023/A:1012102522787
In Vitro Permeability Across Caco-2 Cells (Colonic) Can Predict In Vivo (Small Intestinal) Absorption in Man—Fact or Myth
Shiyin Yee (2004)
10.1023/A:1015807904558
The Madin Darby Canine Kidney (MDCK) Epithelial Cell Monolayer as a Model Cellular Transport Barrier
Moo J. Cho (2004)
10.1021/JM000942E
Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties.
P. Ertl (2000)
A conditionally immortalized epithelial cell line for studies of intestinal drug transport.
S. Tavelin (1999)
10.1023/A:1015092201811
Prediction of the Intestinal Absorption of Endothelin Receptor Antagonists Using Three Theoretical Methods of Increasing Complexity
P. Stenberg (2004)
10.1016/S0928-0987(00)00076-2
Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells.
S. Yamashita (2000)
10.1201/9781420038538.CH4
Tight Junction Permeability to Ions and Water
L. Reuss (2001)
10.1023/A:1022262818573
N-in-One Permeability Studies of Heterogeneous Sets of Compounds Across Caco-2 Cell Monolayers
L. Laitinen (2004)
10.1021/ci990261w
Enhancing the Hit-to-Lead Properties of Lead Optimization Libraries
S. Pickett (2000)
10.1128/AAC.46.5.1375-1380.2002
PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca2+ Channel Blockers
U. Wenzel (2002)
10.1016/0928-0987(95)00007-Z
Co-cultures of human intestinal goblet (HT29-H) and absorptive (Caco-2) cells for studies of drug and peptide absorption
A. Wikman-Larhed (1995)
10.2165/00003088-200241110-00005
Theoretical Predictions of Drug Absorption in Drug Discovery and Development
P. Stenberg (2002)
10.1023/A:1016140429238
Are MDCK Cells Transfected with the Human MDR1 Gene a Good Model of the Human Intestinal Mucosa?
F. Tang (2004)
10.1007/BF02209145
Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat
J. Pappenheimer (2005)



This paper is referenced by
10.1517/17425250902835506
Introduction to computational oral absorption simulation
Kiyohiko Sugano (2009)
1 Metabolism in Drug Development
B. Testa (2014)
10.2174/1389200221666200312104837
Further considerations towards an effective and efficient oncology drug discovery DMPK strategy.
B. Williamson (2020)
10.1517/17425255.3.5.641
Maximising use of in vitro ADMET tools to predict in vivo bioavailability and safety
J. Wang (2007)
10.1007/7355_2009_1
Hit Triage: Medicinal Chemistry Strategies to Improve the Odds of Success in Discovery
K. D. Freeman-Cook (2009)
Development and characterization of a tridimensional intestinal model to study protein drugs absorption
Carla Luis Ribas Costa Pereira (2014)
A Tri-Functionalized Oral Core-Melt Tablet (OCMT) for enhanced delivery of gastro-sensitive proteins and synthetic peptides
Bibi F Choonara (2017)
10.2217/nnm-2020-0085
Oral delivery of natural compounds by phospholipid vesicles.
M. Manconi (2020)
10.1002/9783527627448.CH6
Membrane Permeability – Measurement and Prediction in Drug Discovery
Kiyohiko Sugano (2009)
10.1016/j.biotechadv.2014.07.006
A review of advanced oral drug delivery technologies facilitating the protection and absorption of protein and peptide molecules.
Bibi F Choonara (2014)
10.1002/9783527673261.CH01
Metabolism in Drug Development
B. Testa (2014)
10.1002/HLCA.201200473
Organic stereochemistry. Part 5 : Stereoselectivity in molecular and clinical pharmacology
B. Testa (2013)
10.3109/03639045.2012.669129
New sustained release of Zidovudine Matrix tablets − cytotoxicity toward Caco-2 cells
J. V. Santos (2013)
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