Prediction of the in vitro permeability determined in Caco-2 cells by using artificial neural networks

European Journal of Pharmaceutical Sciences

Volumn 41, Issue 1, 2010, Pages 107-117

  Paixão, Paulo ^a,b   Gouveia, Luís F ^a   Morais, José A G ^a  

^a RESEARCH INSTITUTE FOR MEDICINES IMED ULISBOA   (Portugal)

^b UNIVERSIDADE LUSÓFONA DE HUMANIDADES E TECNOLOGIAS   (Portugal)

Author keywords

Artificial neural network; In silico prediction; In vitro Caco 2 apparent permeability; Molecular descriptors; Pruning of inputs

Indexed keywords

ALFENTANIL; AMOXICILLIN; AMPICILLIN; ARTEMISININ; ARTESUNATE; ATENOLOL; AZITHROMYCIN; BENZOIC ACID; BOSENTAN; BREMAZOCINE; BROMOCRIPTINE; BUDESONIDE; CARBAMAZEPINE; CATECHIN; CEFALEXIN; CEFRADINE; CEFTRIAXONE; CEFUROXIME; CHLORPROMAZINE; CIMETIDINE; CIPROFLOXACIN; CLOZAPINE; COUMARIN; CYMARIN; DESIPRAMINE; DEXAMETHASONE; METHYLDOPA; PARACETAMOL; PHENAZONE; UNINDEXED DRUG;

ARTICLE; ARTIFICIAL NEURAL NETWORK; CELL MEMBRANE PERMEABILITY; CELL STRAIN CACO 2; COMPUTER MODEL; DRUG ABSORPTION; DRUG DEGRADATION; DRUG PENETRATION; IN VITRO STUDY; LIPOPHILICITY; PARTICLE SIZE; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; VALIDATION STUDY; CACO 2 CELL LINE; HUMAN; THEORETICAL MODEL;

CACO-2 CELLS; HUMANS; MODELS, THEORETICAL; NEURAL NETWORKS (COMPUTER);

EID: 77954761477     PISSN: 09280987     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.ejps.2010.05.014     Document Type: Article

References (114)

1. Abraham M.H., Ibrahim A., Zissimos A.M., Zhao Y.H., Comer J., Reynolds D.P. Application of hydrogen bonding calculations in property based drug design. Drug Discov. Today 2002, 7:1056-1063.
2. Alt A., Potthast H., Moessinger J., Sickmuller B., Oeser H. Biopharmaceutical characterization of sotalol-containing oral immediate release drug products. Eur. J. Pharm. Biopharm. 2004, 58:145-150.
3. Amari S., Murata N., Muller K.R., Finke M., Yang H.H. Asymptotic statistical theory of overtraining and cross-validation. IEEE Trans. Neural Network 1997, 8:985-996.
4. Anand B.S., Patel J., Mitra A.K. Interactions of the dipeptide ester prodrugs of acyclovir with the intestinal oligopeptide transporter: competitive inhibition of glycylsarcosine transport in human intestinal cell line-Caco-2. J. Pharmacol. Exp. Ther. 2003, 304:781-791.
5. Artursson P., Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys. Res. Commun. 1991, 175:880-885.
6. Artursson P., Ungell A.L., Lofroth J.E. Selective paracellular permeability in two models of intestinal absorption: cultured monolayers of human intestinal epithelial cells and rat intestinal segments. Pharm. Res. 1993, 10:1123-1129.
7. Behrens I., Kissel T. Do cell culture conditions influence the carrier-mediated transport of peptides in Caco-2 cell monolayers?. Eur. J. Pharm. Sci. 2003, 19:433-442.
8. Bhardwaj R.K., Herrera-Ruiz D., Sinko P.J., Gudmundsson O.S., Knipp G. Delineation of human peptide transporter 1 (hPepT1)-mediated uptake and transport of substrates with varying transporter affinities utilizing stably transfected hPepT1/Madin-Darby canine kidney clones and Caco-2 cells. J. Pharmacol. Exp. Ther. 2005, 314:1093-1100.
9. Briske-Anderson M.J., Finley J.W., Newman S.M. The influence of culture time and passage number on the morphological and physiological development of Caco-2 cells. Proc. Soc. Exp. Biol. Med. 1997, 214:248-257.
10. Butina D. Performance of Kier-hall E-state descriptors in quantitative structure activity relationship (QSAR) studies of multifunctional molecules. Molecules 2004, 9:1004-1009.
11. Caldwell G.W., Easlick S.M., Gunnet J., Masucci J.A., Demarest K. In vitro permeability of eight beta-blockers through Caco-2 monolayers utilizing liquid chromatography/electrospray ionization mass spectrometry. J. Mass Spectrom. 1998, 33:607-614.
12. Camenisch G., Alsenz J., van de Waterbeemd H., Folkers G. Estimation of permeability by passive diffusion through Caco-2 cell monolayers using the drugs' lipophilicity and molecular weight. Eur. J. Pharm. Sci. 1998, 6:317-324.
13. Castillo-Garit J.A., Marrero-Ponce Y., Torrens F., Garcia-Domenech R. Estimation of ADME properties in drug discovery: predicting Caco-2 cell permeability using atom-based stochastic and non-stochastic linear indices. J. Pharm. Sci. 2008, 97:1946-1976.
14. Cataltepe Z., Abu-Mostafa Y.S., Magdon-Ismail M. No free lunch for early stopping. Neural Comput. 1999, 11:995-1009.
15. Cavet M.E., West M., Simmons N.L. Transepithelial transport of the fluoroquinolone ciprofloxacin by human airway epithelial Calu-3 cells. Antimicrob. Agents Chemother. 1997, 41:2693-2698.
16. Crowe A. The influence of P-glycoprotein on morphine transport in Caco-2 cells. Comparison with paclitaxel. Eur. J. Pharmacol. 2002, 440:7-16.
17. Crowe A., Lemaire M. In vitro and in situ absorption of SDZ-RAD using a human intestinal cell line (Caco-2) and a single pass perfusion model in rats: comparison with rapamycin. Pharm. Res. 1998, 15:1666-1672.
18. Da Violante G., Zerrouk N., Richard I., Frendo J.L., Zhiri A., Li-Khuan R., Tricottet V., Provot G., Chaumeil J.C., Arnaud P. Short term Caco-2/TC7 cell culture: comparison between conventional 21-d and a commercially available 3-d system. Biol. Pharm. Bull. 2004, 27:1986-1992.
19. Dearden J., Worth A. In Silico Prediction of Physicochemical Properties. JRC Scientific and Technical Reports 2007, European Commission, Luxembourg.
20. Degim Z. Prediction of permeability coefficients of compounds through Caco-2 cell monolayer using artificial neural network analysis. Drug Dev. Ind. Pharm. 2005, 31:935-942.
21. Di Fenza A., Alagona G., Ghio C., Leonardi R., Giolitti A., Madami A. Caco-2 cell permeability modelling: a neural network coupled genetic algorithm approach. J. Comput. Aided Mol. Des. 2007, 21:207-221.
22. Egan W.J., Merz K.M., Baldwin J.J. Prediction of drug absorption using multivariate statistics. J. Med. Chem. 2000, 43:3867-3877.
23. Ekins S. In silico approaches to predicting drug metabolism, toxicology and beyond. Biochem. Soc. Trans. 2003, 31:611-614.
24. Ekins S., Durst G.L., Stratford R.E., Thorner D.A., Lewis R., Loncharich R.J., Wikel J.H. Three-dimensional quantitative structure-permeability relationship analysis for a series of inhibitors of rhinovirus replication. J. Chem. Inf. Comput. Sci. 2001, 41:1578-1586.
25. Ertl P., Rohde B., Selzer P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J. Med. Chem. 2000, 43:3714-3717.
26. Fagerholm U., Nilsson D., Knutson L., Lennernas H. Jejunal permeability in humans in vivo and rats in situ: investigation of molecular size selectivity and solvent drag. Acta Physiol. Scand. 1999, 165:315-324.
27. Fujikawa M., Ano R., Nakao K., Shimizu R., Akamatsu M. Relationships between structure and high-throughput screening permeability of diverse drugs with artificial membranes: application to prediction of Caco-2 cell permeability. Bioorg. Med. Chem. 2005, 13:4721-4732.
28. Fujikawa M., Nakao K., Shimizu R., Akamatsu M. QSAR study on permeability of hydrophobic compounds with artificial membranes. Bioorg. Med. Chem. 2007, 15:3756-3767.
29. Fujiwara S., Yamashita F., Hashida M. Prediction of Caco-2 cell permeability using a combination of MO-calculation and neural network. Int. J. Pharm. 2002, 237:95-105.
30. Fukada A., Saito H., Inui K. Transport mechanisms of nicotine across the human intestinal epithelial cell line Caco-2. J. Pharmacol. Exp. Ther. 2002, 302:532-538.
31. Furfine E.S., Baker C.T., Hale M.R., Reynolds D.J., Salisbury J.A., Searle A.D., Studenberg S.D., Todd D., Tung R.D., Spaltenstein A. Preclinical pharmacology and pharmacokinetics of GW433908, a water-soluble prodrug of the human immunodeficiency virus protease inhibitor amprenavir. Antimicrob. Agents Chemother. 2004, 48:791-798.
32. Galinis-Luciani D., Nguyen L., Yazdanian M. Is PAMPA a useful tool for discovery?. J. Pharm. Sci. 2007, 96:2886-2892.
33. Gan L.S., Hsyu P.H., Pritchard J.F., Thakker D. Mechanism of intestinal absorption of ranitidine and ondansetron: transport across Caco-2 cell monolayers. Pharm. Res. 1993, 10:1722-1725.
34. Gramatica P., Corradi M., Consonni V. Modelling and prediction of soil sorption coefficients of non-ionic organic pesticides by molecular descriptors. Chemosphere 2000, 41:763-777.
35. Guangli M., Yiyu C. Predicting Caco-2 permeability using support vector machine and chemistry development kit. J. Pharm. Pharm. Sci. 2006, 9:210-221.
36. Hartter S., Huwel S., Lohmann T., Abou El Ela A., Langguth P., Hiemke C., Galla H.J. How does the benzamide antipsychotic amisulpride get into the brain?-an in vitro approach comparing amisulpride with clozapine. Neuropsychopharmacology 2003, 28:1916-1922.
37. He X., Sugawara M., Takekuma Y., Miyazaki K. Absorption of ester prodrugs in Caco-2 and rat intestine models. Antimicrob. Agents Chemother. 2004, 48:2604-2609.
38. Hilgendorf C., Spahn-Langguth H., Regardh C.G., Lipka E., Amidon G.L., Langguth P. Caco-2 versus Caco-2/HT29-MTX co-cultured cell lines: permeabilities via diffusion, inside- and outside-directed carrier-mediated transport. J. Pharm. Sci. 2000, 89:63-75.
39. Hou T.J., Zhang W., Xia K., Qiao X.B., Xu X.J. ADME evaluation in drug discovery. 5. Correlation of Caco-2 permeation with simple molecular properties. J. Chem. Inf. Comput. Sci. 2004, 44:1585-1600.
40. Hu M., Borchardt R.T. Mechanism of L-alpha-methyldopa transport through a monolayer of polarized human intestinal epithelial cells (Caco-2). Pharm. Res. 1990, 7:1313-1319.
41. Hunter J., Jepson M.A., Tsuruo T., Simmons N.L., Hirst B.H. Functional expression of P-glycoprotein in apical membranes of human intestinal Caco-2 cells. Kinetics of vinblastine secretion and interaction with modulators. J. Biol. Chem. 1993, 268:14991-14997.
42. Irvine J.D., Takahashi L., Lockhart K., Cheong J., Tolan J.W., Selick H.E., Grove J.R. MDCK (Madin-Darby canine kidney) cells: a tool for membrane permeability screening. J. Pharm. Sci. 1999, 88:28-33.
43. Jollow D.J., Brodie B.B. Mechanisms of drug absorption and of drug solution. Pharmacology 1972, 8:21-32.
44. Karlsson J., Ungell A., Grasjo J., Artursson P. Paracellular drug transport across intestinal epithelia: influence of charge and induced water flux. Eur. J. Pharm. Sci. 1999, 9:47-56.
45. Kelder J., Grootenhuis P.D.J., Bayada D.M., Delbressine L.P.C., Ploemen J.P. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs. Pharm. Res. 1999, 16:1514-1519.
46. Kerns E.H., Di L., Petusky S., Farris M., Ley R., Jupp P. Combined application of parallel artificial membrane permeability assay and Caco-2 permeability assays in drug discovery. J. Pharm. Sci. 2004, 93:1440-1453.
47. Khan S.I., Abourashed E.A., Khan I.A., Walker L.A. Transport of harman alkaloids across Caco-2 cell monolayers. Chem. Pharm. Bull. (Tokyo) 2004, 52:394-397.
48. Klopman G., Stefan L.R., Saiakhov R.D. ADME evaluation. 2. A computer model for the prediction of intestinal absorption in humans. Eur. J. Pharm. Sci. 2002, 17:253-263.
49. Laitinen L., Kangas H., Kaukonen A.M., Hakala K., Kotiaho T., Kostiainen R., Hirvonen J. N-in-one permeability studies of heterogeneous sets of compounds across Caco-2 cell monolayers. Pharm. Res. 2003, 20:187-197.
50. Lalloo A.K., Luo F.R., Guo A., Paranjpe P.V., Lee S.H., Vyas V., Rubin E., Sinko P.J. Membrane transport of camptothecin: facilitation by human P-glycoprotein (ABCB1) and multidrug resistance protein 2 (ABCC2). BMC Med. 2004, 2:16.
51. Lee K.J., Johnson N., Castelo J., Sinko P.J., Grass G., Holme K., Lee Y.H. Effect of experimental pH on the in vitro permeability in intact rabbit intestines and Caco-2 monolayer. Eur. J. Pharm. Sci. 2005, 25:193-200.
52. Linnankoski J., Makela J.M., Ranta V.P., Urtti A., Yliperttula M. Computational prediction of oral drug absorption based on absorption rate constants in humans. J. Med. Chem. 2006, 49:3674-3681.
53. Lipinski C.A., Lombardo F., Dominy B.W., Feeney P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2001, 46:3-26.
54. Marino A.M., Yarde M., Patel H., Chong S., Balimane P.V. Validation of the 96 well Caco-2 cell culture model for high throughput permeability assessment of discovery compounds. Int. J. Pharm. 2005, 297:235-241.
55. Markowska M., Oberle R., Juzwin S., Hsu C.P., Gryszkiewicz M., Streeter A.J. Optimizing Caco-2 cell monolayers to increase throughput in drug intestinal absorption analysis. J. Pharmacol. Toxicol. Methods 2001, 46:51-55.
56. Martel F., Monteiro R., Lemos C. Uptake of serotonin at the apical and basolateral membranes of human intestinal epithelial (Caco-2) cells occurs through the neuronal serotonin transporter (SERT). J. Pharmacol. Exp. Ther. 2003, 306:355-362.
57. Martin Y.C. A bioavailability score. J. Med. Chem. 2005, 48:3164-3170.
58. Martini L.G., Avontuur P., George A., Willson R.J., Crowley P.J. Solubility parameter and oral absorption. Eur. J. Pharm. Biopharm. 1999, 48:259-263.
59. Masungi C., Borremans C., Willems B., Mensch J., Van Dijck A., Augustijns P., Brewster M.E., Noppe M. Usefulness of a novel Caco-2 cell perfusion system. I. In vitro prediction of the absorption potential of passively diffused compounds. J. Pharm. Sci. 2004, 93:2507-2521.
60. Matthias A., Blanchfield J.T., Penman K.G., Toth I., Lang C.S., De Voss J.J., Lehmann R.P. Permeability studies of alkylamides and caffeic acid conjugates from echinacea using a Caco-2 cell monolayer model. J. Clin. Pharm. Ther. 2004, 29:7-13.
61. Miret S., Abrahamse L., de Groene E.M. Comparison of in vitro models for the prediction of compound absorption across the human intestinal mucosa. J. Biomol .Screen 2004, 9:598-606.
62. Nakao K., Fujikawa M., Shimizu R., Akamatsu M. QSAR application for the prediction of compound permeability with in silico descriptors in practical use. J. Comput. Aided Mol. Des. 2009, 23:309-319.
63. Neuhoff S., Ungell A.L., Zamora I., Artursson P. pH-dependent bidirectional transport of weakly basic drugs across Caco-2 monolayers: implications for drug-drug interactions. Pharm. Res. 2003, 20:1141-1148.
64. Nishimura N., Naora K., Uemura T., Hirano H., Iwamoto K. Transepithelial permeation of tolbutamide across the human intestinal cell line, Caco-2. Drug Metab. Pharmacokinet. 2004, 19:48-54.
65. Nordqvist A., Nilsson J., Lindmark T., Eriksson A., Garberg P., Kihlen M. A general model for prediction of Caco-2 cell permeability. Qsar Comb. Sci. 2004, 23:303-310.
66. Norinder U., Osterberg T. Theoretical calculation and prediction of drug transport processes using simple parameters and partial least squares projections to latent structures (PLS) statistics. The use of electrotopological state indices. J. Pharm. Sci. 2001, 90:1076-1085.
67. Oka A., Oda M., Saitoh H., Nakayama A., Takada M., Aungst B.J. Secretory transport of methylprednisolone possibly mediated by P-glycoprotein in Caco-2 cells. Biol. Pharm. Bull. 2002, 25:393-396.
68. Pachot J.I., Botham R.P., Haegele K.D., Hwang K. Experimental estimation of the role of P-Glycoprotein in the pharmacokinetic behaviour of telithromycin, a novel ketolide, in comparison with roxithromycin and other macrolides using the Caco-2 cell model. J. Pharm. Pharm. Sci. 2003, 6:1-12.
69. Pade V., Stavchansky S. Link between drug absorption solubility and permeability measurements in Caco-2 cells. J. Pharm. Sci. 1998, 87:1604-1607.
70. Paixao P., Gouveia L.F., Morais J.A. Prediction of drug distribution within blood. Eur. J. Pharm. Sci. 2009, 36:544-554.
71. Palm K., Luthman K., Ungell A.L., Strandlund G., Artursson P. Correlation of drug absorption with molecular surface properties. J. Pharm. Sci. 1996, 85:32-39.
72. Palm K., Stenberg P., Luthman K., Artursson P. Polar molecular surface properties predict the intestinal absorption of drugs in humans. Pharm. Res. 1997, 14:568-571.
73. Polli J.E., Ginski M.J. Human drug absorption kinetics and comparison to Caco-2 monolayer permeabilities. Pharm. Res. 1998, 15:47-52.
74. Ponce Y.M., Perez M.A.C., Zaldivar V.R., Diaz H.G., Torrens F. A new topological descriptors based model for predicting intestinal epithelial transport of drugs in Caco-2 cell culture. J. Pharm. Pharm. Sci. 2004, 7:186-199.
75. Prechelt L. Automatic early stopping using cross validation: quantifying the criteria. Neural Networks 1998, 11:761-767.
76. Raoof A.A., Augustijns P.F., Verbeeck R.K. In vivo assessment of intestinal, hepatic, and pulmonary first pass metabolism of propofol in the rat. Pharm. Res. 1996, 13:891-895.
77. Ribadeneira M.D., Aungst B.J., Eyermann C.J., Huang S.M. Effects of structural modifications on the intestinal permeability of angiotensin II receptor antagonists and the correlation of in vitro, in situ, and in vivo absorption. Pharm. Res. 1996, 13:227-233.
78. Rubas W., Jezyk N., Grass G.M. Comparison of the permeability characteristics of a human colonic epithelial (Caco-2) cell line to colon of rabbit, monkey, and dog intestine and human drug absorption. Pharm. Res. 1993, 10:113-118.
79. Saitoh R., Sugano K., Takata N., Tachibana T., Higashida A., Nabuchi Y., Aso Y. Correction of permeability with pore radius of tight junctions in Caco-2 monolayers improves the prediction of the dose fraction of hydrophilic drugs absorbed by humans. Pharm. Res. 2004, 21:749-755.
80. Santos-Filho O.A., Hopfinger A.J. Combined 4D-fingerprint and clustering based membrane-interaction QSAR analyses for constructing consensus Caco-2 cell permeation virtual screens. J. Pharm. Sci. 2008, 97:566-583.
81. So S.S., Richards W.G. Application of neural networks: quantitative structure-activity relationships of the derivatives of 2,4-diamino-5-(substituted-benzyl)pyrimidines as DHFR inhibitors. J. Med. Chem. 1992, 35:3201-3207.
82. Soldner A., Benet L.Z., Mutschler E., Christians U. Active transport of the angiotensin-II antagonist losartan and its main metabolite EXP 3174 across MDCK-MDR1 and Caco-2 cell monolayers. Br. J. Pharmacol. 2000, 129:1235-1243.
83. Stenberg P., Bergstrom C.A., Luthman K., Artursson P. Theoretical predictions of drug absorption in drug discovery and development. Clin. Pharmacokinet. 2002, 41:877-899.
84. Stenberg P., Norinder U., Luthman K., Artursson P. Experimental and computational screening models for the prediction of intestinal drug absorption. J. Med. Chem. 2001, 44:1927-1937.
85. Sun B.W., Zhao X.C., Wang G.J., Li N., Li J.S. Hormonal regulation of dipeptide transporter (PepT1) in Caco-2 cells with normal and anoxia/reoxygenation management. World J. Gastroenterol. 2003, 9:808-812.
86. Sun D., Lennernas H., Welage L.S., Barnett J.L., Landowski C.P., Foster D., Fleisher D., Lee K.D., Amidon G.L. Comparison of human duodenum and Caco-2 gene expression profiles for 12,000 gene sequences tags and correlation with permeability of 26 drugs. Pharm. Res. 2002, 19:1400-1416.
87. Sutherland J.J., O'Brien L.A., Weaver D.F. A comparison of methods for modeling quantitative structure-activity relationships. J. Med. Chem. 2004, 47:5541-5554.
88. Tammela P., Laitinen L., Galkin A., Wennberg T., Heczko R., Vuorela H., Slotte J.P., Vuorela P. Permeability characteristics and membrane affinity of flavonoids and alkyl gallates in Caco-2 cells and in phospholipid vesicles. Arch. Biochem. Biophys. 2004, 425:193-199.
89. Tannergren C. Intestinal Permeability and Presystemic Extraction of Fexofenadine and R/S-verapamil 2004, Department of Pharmacy, Uppsala University, Uppsala, pp. 58.
90. Tetko I.V., Bruneau P. Application of ALOGPS to predict 1-octanol/water distribution coefficients, logP, and logD, of AstraZeneca in-house database. J. Pharm. Sci. 2004, 93:3103-3110.
91. Tetko I.V., Gasteiger J., Todeschini R., Mauri A., Livingstone D., Ertl P., Palyulin V.A., Radchenko E.V., Zefirov N.S., Makarenko A.S., Tanchuk V.Y., Prokopenko V.V. Virtual computational chemistry laboratory-design and description. J. Comput. Aided Mol. Des. 2005, 19:453-463.
92. Tetko I.V., Villa A.E.P., Livingstone D.J. Neural network studies. 2. Variable selection. J. Chem. Inf. Comp. Sci. 1996, 36:794-803.
93. Todeschini R., Consonni V. Handbook of Molecular Descriptors 2000, Wiley-VCH, Weinheim.
94. Tronde A. Pulmonary Drug Absorption: In Vitro and In Vivo Investigations of Drug Absorption Across the Lung Barrier and its Relation to Drug Physicochemical Properties 2002, Department of Pharmacy, Uppsala University, Uppsala, pp. 86.
95. Turner J.V., Maddalena D.J., Cutler D.J. Pharmacokinetic parameter prediction from drug structure using artificial neural networks. Int. J. Pharm. 2004, 270:209-219.
96. Vaidyanathan J.B., Walle T. Cellular uptake and efflux of the tea flavonoid (-)epicatechin-3-gallate in the human intestinal cell line Caco-2. J. Pharmacol. Exp. Ther. 2003, 307:745-752.
97. van de Waterbeemd H., Camenisch G., Folkers G., Chretien J.R., Raevsky O.A. Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J. Drug Target 1998, 6:151-165.
98. Venkatesh S., Lipper R.A. Role of the development scientist in compound lead selection and optimization. J. Pharm. Sci. 2000, 89:145-154.
99. Verma R.P., Hansch C., Selassie C.D. Comparative QSAR studies on PAMPA/modified PAMPA for high throughput profiling of drug absorption potential with respect to Caco-2 cells and human intestinal absorption. J. Comput. Aided Mol. Des. 2007, 21:3-22.
100. Vogel H.G. Drug Discovery and Evaluation-Safety and Pharmacokinetic Assays 2006, Springer-Verlag, Berlin.
101. Volpe D.A. Variability in Caco-2 and MDCK cell-based intestinal permeability assays. J. Pharm. Sci. 2007.
102. Votano J.R., Parham M., Hall L.H., Kier L.B., Hall L.M. Prediction of aqueous solubility based on large datasets using several QSPR models utilizing topological structure representation. Chem. Biodiversity 2004, 1:1829-1841.
103. Watson C.J., Rowland M., Warhurst G. Functional modeling of tight junctions in intestinal cell monolayers using polyethylene glycol oligomers. Am. J. Physiol. Cell Physiol. 2001, 281:C388-C397.
104. Winiwarter S., Ax F., Lennernas H., Hallberg A., Pettersson C., Karlen A. Hydrogen bonding descriptors in the prediction of human in vivo intestinal permeability. J. Mol. Graph Model 2003, 21:273-287.
105. Winiwarter S., Bonham N.M., Ax F., Hallberg A., Lennernas H., Karlen A. Correlation of human jejunal permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate data analysis approach. J. Med. Chem. 1998, 41:4939-4949.
106. Winkler D.A. Neural networks as robust tools in drug lead discovery and development. Mol. Biotechnol. 2004, 27:139-168.
107. Wong A.K., Ross B.P., Chan Y.N., Artursson P., Lazorova L., Jones A., Toth I. Determination of transport in the Caco-2 cell assay of compounds varying in lipophilicity using LC-MS: enhanced transport of Leu-enkephalin analogues. Eur. J. Pharm. Sci. 2002, 16:113-118.
108. Yamashita F., Fujiwara S., Hashida M. The " latent membrane permeability" concept: QSPR analysis of inter/intralaboratory variable Caco-2 permeability. J. Chem. Inf. Comput. Sci. 2002, 42:408-413.
109. Yamashita F., Wanchana S., Hashida M. Quantitative structure/property relationship analysis of Caco-2 permeability using a genetic algorithm-based partial least squares method. J. Pharm. Sci. 2002, 91:2230-2239.
110. Yang H.T., Wang G.J. Transport and uptake characteristics of a new derivative of berberine (CPU-86017) by human intestinal epithelial cell line: Caco-2. Acta Pharmacol. Sin 2003, 24:1185-1191.
111. Yazdanian M., Glynn S.L., Wright J.L., Hawi A. Correlating partitioning and Caco-2 cell permeability of structurally diverse small molecular weight compounds. Pharm. Res. 1998, 15:1490-1494.
112. Yee S. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man-fact or myth. Pharm. Res. 1997, 14:763-766.
113. Zhao Y.H., Le J., Abraham M.H., Hersey A., Eddershaw P.J., Luscombe C.N., Butina D., Beck G., Sherborne B., Cooper I., Platts J.A. Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure-activity relationship (QSAR) with the Abraham descriptors. J. Pharm. Sci. 2001, 90:749-784.
114. Zhou S., Feng X., Kestell P., Baguley B.C., Paxton J.W. Determination of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid and its acyl glucuronide in Caco-2 monolayers by liquid chromatography with fluorescence detection: application to transport studies. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2004, 809:87-97.