Caco-2 monolayers in experimental and theoretical predictions of drug transport

Advanced Drug Delivery Reviews

Volumn 22, Issue 1-2, 1996, Pages 67-84

  Artursson, Per ^a   Palm, Katrin ^a   Luthman, Kristina ^a  

^a UPPSALA UNIVERSITY   (Sweden)

Author keywords

Caco 2; cell monolayer; desolvation energy; drug absorption; drug transport; hydrogen bonding potential; in vitro in vivo correlation; intestinal epithelium; molecular surface area; partition coefficient

Indexed keywords

CELLS; DRUG PRODUCTS; HYDROGEN BONDS; MONOLAYERS; PHARMACOKINETICS;

CACO 2 MONOLAYERS; CELL MONOLAYER; DESOLVATION ENERGY; DRUG ABSORPTION; IN VITRO IN VIVO CORRELATION; INTESTINAL EPITHELIUM; MOLECULAR SURFACE AREA; PARTITION COEFFICIENT;

DRUG THERAPY;

ATENOLOL; CYANOCOBALAMIN; FLUOROURACIL; LEVODOPA; METOPROLOL; NAPROXEN; PHENAZONE; TERBUTALINE;

CELL STRAIN CACO 2; DRUG ABSORPTION; DRUG RESEARCH; DRUG TRANSPORT; HUMAN; HUMAN CELL; INTESTINE ABSORPTION; MEMBRANE PERMEABILITY; MODEL; MONOLAYER CULTURE; PARTITION COEFFICIENT; PHYSICAL CHEMISTRY; PREDICTION; PRIORITY JOURNAL; REVIEW;

EID: 0030588714     PISSN: 0169409X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0169-409X(96)00415-2     Document Type: Review

References (113)

1. [1] Artursson, P. (1991) Cell cultures as models for drug absorption across the intestinal mucosa. Crit. Rev. Ther. Drug Carrier Syst. 8, 305-330.
2. [2] Hillgren, K.M., Kato, A. and Borchardt, R.T. (1995) In vitro systems for studying intestinal drug absorption. Med. Res. Rev. 15, 83-109.
3. [3] Burton, P.S., Conradi, R.A., Hilgers, A.R. and Ho, N.F.H. (1993) Evidence for a polarized efflux system for peptides in the apical membrane of Caco-2 cells. Biochem. Biophys. Res. Commun. 190, 760-766.
4. [4] Karlsson, J., Kuo, S.-M., Ziemniak, J, and Artursson, P. (1993) Transport of celiprolol across human intestinal epithelial Caco-2 cells: mediation of secretion by multiple transporters including P-glycoprotein. Br. J. Pharmacol. 110, 1009-1016.
5. [5] Takanaga, H., Tamai, I. and Tsuji, A. (1994) pH-dependent and carrier-mediated transport of salicylic acid across Caco-2 cells. J. Pharm. Pharmacol. 46, 567-570.
6. [6] Matsumoto, S.-I., Saito, H. and Inui, K.-I. (1994) Transcellular transport of oral cephalosporins in human intestinal epithelial cells, Caco-2: Interaction with dipepticle transport systems in apical and basolateral membranes. J. Pharmacol. Exp. Ther. 270, 498-504.
7. [7] Dantzig, A.H., Hoskins, J., Tabas, L.B., Bright, S., Shepard, R.L., Jenkins, I.L., Duckworth, D.C., Sportsman, J.R., Mackensen, D., Rosteck Jr., P.R. and Skatrud, P.L. (1994) Association of intestinal peptide transport with a protein related to the cadherin superfamily. Science 264, 430-433.
8. [8] Hunter, J., Jepson, M.A., Tsuruo, T., Simmons, N.L. and Hirst, B.H. (1993) Functional expression of P-glycoprotein in apical membranes of human intestinal Caco-2 cells. J. Biol. Chem. 268, 14991-14997.
9. A with P-glycoprotein in human intestinal epithelial cells. Eur. J. Pharmacol. 288, 187-192.
10. [10] Artursson, P. and Karlsson, J. (1991) Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. Biochem. Biophys. Res. Commun. 175, 880-885.
11. [11] Rubas, W., Villagran, J., Cromwell, M., McLeod, A., Wassenberg, J. and Mrsny, R. (1995) Correlation of solute flux across Caco-2 monolayers and colonic tissue in vitro. S.t.p. pharma Sci. 5, 93-97.
12. [12] Wils, P., Warnery, A., Phung-Ba, V. and Scherman, D. (1994) Differentiated intestinal epithelial cell lines as in vitro models for predicting the intestinal absorption of drugs. Cell Biol. Toxicol. 10, 393-397.
13. [13] Stevenson, C.L., Augustijns, P.F. and Hendren, R.W. (1995) Permeability screen for synthetic peptide combinatorial libraries using Caco-2 cell monolayers and LC/MS/MS. Pharm. Res. 12, S-94.
14. [14] Kuhfeld, M.T., Hinshaw, M.E., Stratford, R.E. and Zynger, J. (1994) An automated in vitro permeability screen using robotics. Pharm. Res. 11, S-39.
15. [15] Pappenheimer, J.R. and Reiss, K.Z. (1987) Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat. J. Membr. Biol. 100, 123-136.
16. [16] Nellans, H.N. (1991) Paracellular intestinal transport: Modulation of absorption. Adv. Drug Deliv. Rev. 7, 339-364.
17. [17] Furuse, M., Hirase, T., Itoh, M., Nagafuchi, A., Yonemura, S., Tsukita, S. and Tsukita, S. (1993) Occludin: a novel integral membrane protein localizing at tight junctions. J. Cell Biol. 123, 1777-1788.
18. [18] Lee, V.H.L., Yamamoto, A. and Kompella, U.B. (1991) Mucosal penetration enhancers for facilitation of peptide and protein drug absorption. Crit. Rev. Ther. Drug Carrier Syst. 8, 91-192.
19. [19] Hochman, J. and Artursson, P. (1994) Mechanisms of absorption enhancement and tight junction regulation. J. Control. Release 29, 253-267.
20. [20] Lennernäs, H., Nilsson, D., Aquilonius, S.-M., Ahrenstedt, Ö., Knutson, L. and Paalzow, L.K. (1993) The effect of L-leucin on the absorption of levodopa, studied by regional jejeunal perfusion in man. Br. J. Clin. Pharmacol. 35, 243-250.
21. [21] Gan, L.-S., Eads, C., Niederer, T., Bridgers, A., Yanni, S., Hsyu, P.-H., Pritchard. F.J. and Thakker, D. (1994) Use of Caco-2 cells as in vitro intestinal absorption and metabolism model. Drug Dev. Ind. Pharm. 20, 615-631.
22. [22] Augustinjs, P.F., Bradshaw, T.P., Gan, L.-S.L., Hendren, R.W. and Thakker, D.R. (1993) Evidence for a polarized efflux system in Caco-2 cells capable of modulating cyclosporin A transport. Biochem. Biophys. Res. Commun. 197, 360-365.
23. [23] de Aizpurua, H.J. and Russel-Jones, G.I. (1988) Oral vaccination. Identification of classes of proteins that provoke an immune response upon oral feeding. J. Exp. Med. 167, 440-451.
24. [24] Heyman, M., Ducroc, R., Desjeux, J.-F. and Morgat, J.L. (1982) Horseradish peroxidase transport across adult rabbit jejunum in vitro. Am. J. Physiol. 242, G558-G564.
25. [25] Heyman, M., Crain-Denoyelle, A.-M., Nath, S.K. and Desjeux, J.-F. (1990) Quantification of protein transcytosis in the human colon carcinoma cell line Caco-2. J. Cell. Physiol. 143, 391-395.
26. [26] Taub, M.E. and Shen, W.-C. (1992) Polarity in the transcytotic processing of apical and basal membrane-bound peroxidase-polylysine conjugates in MDCK cells. J. Cell. Physiol. 150, 283-290.
27. [27] Lehr, C.-M. and Lee, V.H.L. (1993) Binding and transport of some bioadhesive plant lectins across Caco-2 cell monolayers. Pharm. Res. 10, 1796-1799.
28. [28] Mikogami, T., Heyman, M., Spik, G. and Desjeux, J.-F. (1994) Apical-to-basolateral transepithelial transport of human lactoferrin in the intestinal cell line HT-29cl.19A. Am. J. Physiol. 267, G308-G315.
29. [29] Lazorová, L., Sjölander, A., Russel-Jones, G.J., Linder, J. and Artursson, P. (1993) Intestinal tissue distribution and epithelial transport of the oral immunogen LTB, the B subunit of E. coli heat-labile enterotoxin. J. Drug Targeting 1, 331-340.
30. [30] Lazorová, L., Artursson, P., Engström, Å. and Sjölander, A. (1996) Transport of an influenza virus vaccine formulation (iscom) in human intestinal epithelial (Caco-2) cells. Am. J. Physiol. 270, G554-G564.
31. [31] Dix, C.J., Hassan, I.F., Obray, H.Y., Shah, R. and Wilson, G. (1990) The transport of vitamin B12 through polarized monolayers of Caco-2 cells. Gastroenterology 98, 1272-1279.
32. [32] Krachenbuhl, J.-P. and Neutra, M.R. (1992) Molecular and cellular basis of immune protection of mucosal surfaces. Physiol. Rev. 72, 853-879.
33. [33] O'Hagan, D.T. (1994) Oral immunization and the common mucosal immune system. In: D.T. O'Hagan (Ed.), Novel Delivery Systems for Oral Vaccines. CRC Press, Boca Raton, FL, pp. 1-24.
34. [34] Kim, D.-C., Burton, P.S. and Borchardt, R.T. (1993) A correlation between the permeability characteristics of a series of peptides using an in vitro cell culture model (Caco-2) and those using an in situ perfused rat ileum model of the intestinal mucosa. Pharm. Res. 10, 1710-1714.
35. [35] Conradi, R.A., Wilkinson, K.F., Rush, B.D., Hilgers, A.R., Ruwart, M.J. and Burton. P.S. (1993) In vitro/in vivo models for peptide oral absorption: Comparison of Caco-2 cell permeability with rat intestinal absorption of renin inhibitory peptides. Pharm. Res. 10, 1790-1792.
36. [36] Lennernäs, H., Palm, K., Fagerholm, U. and Artursson, P. (1996) Correlation between paracellular and transcellular drug permeability in the human jejunum and Caco-2 monolayers. Int. J. Pharm. 127, 103-107.
37. [37] Lennernäs, H., Ahrenstedt, Ö., Hällgren, R., Knutson, L., Ryde, M. and Paalzow, L.K. (1992) Regional jejunal perfusion, a new in vivo approach to study oral drug absorption in man. Pharm. Res. 9, 1243-1251.
38. [38] Amidon, G.L., Lennernäs, H., Shah, V.P. and Crison, J.R. (1995) A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12, 413-420.
39. [39] Hu, M, Sinko, P.J., de Meere, A.L., Johnson, D.A. and Amidon, G.L. (1988) Membrane permeability parameters for some amino acids and beta-lactam antibiotics: Application of the boundary layer approach. J. Theor. Biol. 131, 107-114.
40. [40] Karlsson, J. and Artursson, P. (1991) 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. Int. J. Pharm. 71, 55-64.
41. [41] Wilson, F.A. and Dictschy, J.M. (1974) The intestinal unstirred water layer: its surface area and effect on active transport kinetics. Biochim. Biophys. Acta 363, 112-126.
42. [42] Pinto, M., Robine-Leon, S., Appay, M.-D., Kedinger, M., Triadou, N., Dussaulx, E., Lacroix, B., Simon-Assmann, P., Haffen, K., Fogh, J. and Zweibaum, A. (1983) Enterocyte-like differentiation and polarization of the human colon carcinoma cell line Caco-2 in culture. Biol. Cell 47, 323-330.
43. [43] Hidalgo, I.J., Raub, T.J. and Borchardt, R.T. (1989) Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology 96, 736-749.
44. [44] Artursson, P. (1990) Epithelial transport of drugs I. A model for studying the transport of drugs (β-blocking agents) over an intestinal epithelial cell line (Caco-2). J. Pharm. Sci. 79, 476-482.
45. [45] Artursson, P., Ungell, A.-L. and Löfroth, J.-E. (1993) Selective paracellular permeability in two models of intestinal absorption: cultured monolayers of human intestinal epithelial cells and rat intestinal segments. Pharm. Res. 10, 1123-1129.
46. [46] Tanaka, Y., Taki, Y., Sakane, T., Nadai, T., Sezaki, H. and Yamashita, S. (1995) Characterization of drug transport through tight-junclional pathway in Caco-2 monolayer: Comparison with isolated rat jejunum and colon. Pharm. Res. 12, 523-528.
47. [47] Madara, J.L. and Hecht, G. (1989) Tight (occluding) junctions in cultured (and native) epithelial cells. In: K.S. Matlin and J.D. Valentich (Eds.), Functional Epithelial Cells in Culture. Alan R. Liss, New York, pp. 131-163.
48. [48] Lencer, W.I., Delp, C., Neutra, M.R. and Madara, J.L. (1992) Mechanism of cholera toxin action on a polarized human intestinal epithelial cell line: role of vesicular traffic. J. Cell Biol. 117, 1197-1209.
49. [49] Jodal, M., Holmgren, S., Lundgren, O. and Sjöqvist, A. (1993) Involvement of the mycentric plexus in the cholera toxin-induced net fluid secretion in the rat small intestine. Gastroenterology 105, 1286-1293.
50. [50] Madara, J.L. and Pappenheimer, J.R. (1987) Structural basis for physiological regulation of paracellular pathways in intestinal epithelia. J. Membr. Biol. 100, 149-164.
51. [51] Fleisher, D., Sheth, N., Griffin, H., McFadden, M. and Aspacher, G. (1989) Nutrient influences on rat intestinal phenytoin uptake. Pharm. Res. 6, 332-337.
52. [52] Fine, K.D., Santa Ana, C.A., Porter, J.L. and Fordtran, J.S. (1994) Mechanism by which glucose stimulates the passive absorption of small solutes by the human jejunum in vivo. Gastroenterology 107, 389-395.
53. [53] Lennernäs, H., Ahrenstedt, Ö. and Ungell, A.-L. (1994) Intestinal drug absorption during induced net water absorption in man: a mechanistic study using antipyrine, atenolol and enalaprilat. Br. J. Clin. Pharmacol. 37, 589-596.
54. [54] Karlsson, J., Ungell, A.-L. and Artursson, P. (1994) Effect of an oral rehydration solution on paracellular drug transport in intestinal epithelial cells and tissues: Assessment of charge and tissue selectivity. Pharm. Res. 11, S-248.
55. [55] Walter, E., Kissel, T., Reers, M., Dickneite, G., Hoffmann, D. and Stüber, W. (1995) Transepithelial transport properties of peptidomimetic thrombin inhibitors in monolayers of a human intestinal cell line (Caco-2) and their correlation to in vivo data. Pharm. Res. 12, 360-365.
56. [56] Ma, T.Y., Hollander, D., Bhalla, D., Nguyen, H. and Krugliak, P. (1992) IEC-18, a nontransformed small inteslinal cell line for studying epithelial permeability. J. Lab. Clin. Med. 120, 329-341.
57. [57] Duizer, E., Stenhuis, W.S., Penninks, A.H. and Groten, J.P. (1995) Transport of compounds across monolayers of intestinal cell lines: Comparison of IEC-18 and Caco-2. Ital. J. Gastroenterol. 27, 154.
58. [58] Paul, E.C.A., Hochman, J. and Quaroni, A. (1993) Conditionally immortalized intestinal epithelial cells: novel approach for study of differentiated enterocytes. Am. J. Physiol. 265, C266-C278.
59. [59] Milovic, V., Olsson, S., Hochman, J., Paul, E.C.A. and Artursson, P. (1996) Conditionally immortalized rat fetal intestinal cell line (2/4/A1) for studying epithelial differentiation, apoptosis and permeability. Gastroenterology 110, A822.
60. [60] Wikman-Larhed, A. and Artursson, P. (1995) Co-cultures of human intestinal goblet (HT29-H) and absorptive (Caco-2) cells for studies of drug and peptide absorption. Eur. J. Pharm. Sci. 3, 171-183.
61. [61] Wikman, A., Karlsson, J., Carlstedt, I. and Artursson, P. (1993) A drug absorption model based on the mucus layer producing human intestinal epithelial goblet cell hue HT29-H. Pharm. Res. 10, 843-852.
62. [62] González-Mariscal, L., Chávez de Ramirez, B., Lázaro, A. and Cereijido, M. (1989) Establishment of tight junctions between cells from different animal species and different sealing capacities. J. Membr. Biol. 107, 43-56.
63. b-tsA58. Proc. Natl. Acad. Sci. USA 90, 587-591.
64. [64] Hidalgo, I.J. and Borchardt, R.T. (1990) Transport of a large neutral ammo acid (phenylalanine) in a human intestinal epithelial cell line: Caco-2. Biochim. Biophys. Acta 1028, 25-30.
65. [65] Hu, M. and Borchardt, R.T. (1990) Mechanism of L-α-methyldopa transport through a monolayer of polarized human intestinal epithelial cells (Caco-2). Pharm. Res. 7, 1313-1319.
66. [66] Stewart, B.H., Chan, O.H., Lu, R.H., Reyner, E.L., Schmid, H.L., Hamilton, H.W., Steinbaugh, B.A. and Taylor, M.D. (1995) Comparison of intestinal permeabilities determined in multiple in vitro and in situ models: Relationship to absorption in humans. Pharm. Res. 12, 693-699.
67. [67] Lennernäs, H. and Regårdh, C.G. (1993) Evidence for an interaction between the beta-blocker pafenolol and bile salts in the intestinal lumen of the rat leading to dose-dependent oral absorption and double peaks in the plasma concentration-time profile. Pharm. Res. 10, 879-883.
68. [68] Yamaguchi, T., Ikeda, C. and Sekine, Y. (1986) Intestinal absorption of a beta-adrenergic blocking agent nadolol. II. Mechanism of the inhibitory effect on the intestinal absorption of nadolol by sodium cholate in rats. Chem. Pharm. Bull. 34, 3836-3843.
69. [69] Karlsson, J., Wikman, A. and Artursson, P. (1993) The mucus layer as a barrier to drug absorption in monolayers of human intestinal epithelial HT29-H goblet cells. Int. J. Pharm. 99, 209-218.
70. [70] Vachon, P.H. and Beaulieu, J.-F. (1992) Transient mosaic patterns of morphological and functional differentiation in the Caco-2 cell line. Gastroenterology 103, 414-423.
71. [71] Walter, E. and Kissel, T. (1994) Transepithelial transport and metabolism of thyrotropin-releasing hormone (TRH) in monolayers of a human intestinal cell line (Caco-2): Evidence for an active transport component? Pharm. Res. 11, 1575-1580.
72. [72] Walter, E. and Kissel, T. (1995) Heterogeneity in the human intestinal cell line Caco-2 leads to differences in transepithelial transport. Eur. J. Pharm. Sci. 3, 215-230.
73. [73] Wilson, G., Hassan, I.F., Dix, C.J., Williamson, I., Shah, R., MacKay, M. and Artursson, P. (1990) Transport and permeability properties of human Caco-2 cells: an in vitro model of the intestinal epithelial cell barrier. J. Control. Release 11, 25-40.
74. [74] Nicklin, P., Irwin, B., Hassan, I., Williamson, I. and Mackay, M. (1992) Permeable support type influences the transport of compounds across Caco-2 cells. Int. J. Pharm. 83, 197-209.
75. [75] Jumarie, C. and Malo, C. (1991) Caco-2 cells cultured in serum-free medium as a model for the study of enterocytic differentiation in vitro. J. Cell. Physiol. 149, 24-33.
76. [76] Artursson, P., Karlsson, J., Ocklind, G. and Schipper, N. (1996) Models of absorptive epithelia for studying transport processes. In: E. Shaw (Ed.), Cell Models of Epithelial Tissues - A Practical approach. I.R.L., Oxford, pp. 111-133.
77. [77] Cogburn, J.N., Donovan, M.G. and Schasteen, C.S. (1991) A model of human small intestinal absorptive cells. 1. Transport barrier. Pharm. Res. 8, 210-216.
78. [78] Rubas, W., Jezyk, N. and Grass, G.M. (1993) 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. 10, 113-118.
79. [79] Martin, Y.C. (1981) A practitioner's perspective of the role of quantitative structure-activity analysis in medicinal chemistry. J. Med. Chem. 24, 229-237.
80. 2 receptor histamine antagonists. J. Med. Chem. 31, 656-671.
81. [81] Conradi, R.A., Hilgers, A.R., Ho, N.F.H. and Burton, P.S. (1991) The influence of peptide structure on transport across Caco-2 cells. Pharm. Res. 8, 1453-1460.
82. [82] Burton, P.S., Conradi, R.A., Hilgers, A.R., Ho, N.F.H. and Maggiora, L.L. (1992) The relationship between peptide structure and transport across epithelial cell monolayers. J. Control. Release 19, 87-98.
83. [83] Wright, L.L. and Painter, G.R. (1992) Role of desolvation energy in the nonfacilitated membrane permeability of dideoxyribose analogs of thymidine. Mol. Pharmacol. 41, 957-962.
84. [84] Barlow, D. and Satoh, T. (1994) The design of peptide analogues for improved absorption. J. Control. Release 29, 283-291.
85. [85] van de Waterbeemd, H. and Kansy, M. (1992) Hydrogen-bonding capacity and brain penetration. Chimia 46, 299-303.
86. [86] Seelig, A., Gottschlich, R. and Devant, R.M. (1994) A method to determine the ability of drugs to diffuse through the blood-brain barrier. Proc. Natl. Acad. Sci. USA 91, 68-72.
87. [87] Mannhold, R., Dross, K.P. and Rekker, R.F. (1990) Drug lipophilicity in QSAR practice: I. A comparison of experimental with calculative approaches. Quant. Struct.-Act. Relatsh. 9, 21-28.
88. [88] Meylan, W.M. and Howard, P.H. (1995) Atom/fragment contribution method for estimating octanol-water partition coefficients. J. Pharm. Sci. 84, 83-92.
89. [89] Gaillard, P., Carrupt, P.-A., Testa, B. and Boudon, A. (1994) Molecular lipophilicity potential, a tool in 3D QSAR: method and applications. J. Comput. Aided Mol. Des. 8, 83-96.
90. [90] Potts, R.O. and Guy, R.H. (1993) The influence of molecular volume and hydrogen-bonding on peptide transport across epithelial membranes. Pharm. Res. 10, 635-636.
91. [91] Burton, P.S., Ho, N.F.H., Conradi, R.A. and Hilgers, A.R. (1993) Reply to the comments by Drs. Potts and Guy. Pharm. Res. 10, 636-637.
92. 1-antihistaminic agents in relation to their central sedative side-effects. Eur. J. Pharm. Sci. 2, 373-384.
93. [93] van de Waterbeemd, H., Camenisch, G., Folkers, G. and Raevsky, O.A. (1996) Estimation of Caco-2 cell permeability using calculated molecular descriptors. Quant. Struct.-Act. Relatsh., submitted.
94. (94) Wils, P., Warnery, A., Phung-Ba, V., Legrain, S. and Scherman, D. (1994) High lipophilicity decreases drug transport across intestinal epithelial cells. J. Pharmacol. Exp. Ther. 269, 654-658.
95. [95] Raub, T.J., Barsuhn, C.L., Williams, L.R., Deckers, D.E., Sawada, G.A. and Ho, N.F.H. (1993) Use of a biophysical-kinetic model to understand the roles of protein binding and membrane partitioning on passive diffusion of highly lipophilic molecules across cellular barriers. J. Drug Targeting 1, 269-286.
96. [96] Sawada, G.A., Ho, N.F.H., Williams, L.R., Barsuhn, C.L. and Raub, T.J. (1994) Transcellular permeability of chlorpromazine demonstrating the roles of protein binding and membrane partitioning. Pharm. Res. 11, 665-673.
97. [97] Taylor, D.C., Pownall, R. and Burke, W. (1985) The absorption of β-adrenoceptor antagonists in rat in-situ small intestine; the effect of lipophilicity. J. Pharm. Pharmacol. 37, 280-283.
98. [98] Buur, A., Trier, L., Magnusson, C. and Artursson, P. (1996) Permeability of 5-fluorouracil and prodrugs in Caco-2 cell monolayers. Int. J. Pharm. 129, 223-231.
99. [99] Hilgers, A.R., Conradi, R.A. and Burton, P.S. (1990) Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa. Pharm. Res. 7, 902-910.
100. [100] Hovgaard, L., Brøndstedt, H., Buur, A. and Bundgaard, H. (1995) Drug delivery studies in Caco-2 monolayers. Synthesis, hydrolysis, and transport of O-cyclopropane carboxylic acid ester prodrugs of various β-blocking agents. Pharm. Res. 12, 387-392.
101. [101] Franks, N.P., Abraham, M.H. and Lieb, W.R. (1993) Molecular organization of liquid n-octanol: An X-ray diffraction analysis. J. Pharm. Sci. 82, 466-470.
102. [102] Pidgeon, C., Ong, S., Liu, H., Qiu, X., Pidgeon, M., Dantzig, A.H., Munroe, J., Hornback, W.J., Kasher, J.S., Glunz, L. and Szczerba, T. (1995) IAM chromatography: an in vitro screen for predicting drug membrane permeability. J. Med. Chem. 38, 590-594.
103. [103] Beigi, F., Yang, Q. and Lundahl, P. (1995) Immobilized-liposome chromatographic analysis of drug partitioning into lipid bilayers. J. Chromatogr. A 704, 315-321.
104. [104] Conradi, R.A., Hilgers, A.R., Ho, N.F.H. and Burton, P.S. (1992) The influence of peptide structure on transport across Caco-2 cells. II. Peptide bond modification which results in improved permeability. Pharm. Res. 9, 435-439.
105. [105] Chikhale, E.G., Ng, K.-Y., Burton, P.S. and Borchardt, R.T. (1994) Hydrogen bonding potential as a determinant of the in vitro and in situ blood-brain barrier permeability of peptides. Pharm. Res. 11, 412-419.
106. [106] Stein, W.D, (1967) The molecular basis of diffusion across cell membranes. In: The Movement of Molecules Across Cell Membranes. Academic Press, London, pp. 65-125.
107. [107] Ooi, T., Oobatake, M., Némethy, G. and Scheraga, H.A. (1987) Accessible surface areas as a measure of the thermodynamic parameters of hydration of peptides. Proc. Natl. Acad. Sci. USA 84, 3086-3090.
108. [108] Dunn III, W.J., Koehler, M.G. and Grigoras, S. (1987) The role of solvent-accessible surface area in determining partition coefficients. J. Med. Chem. 30, 1121-1126.
109. [109] Lipkowitz, K.B., Baker, B. and Larter, R. (1989) Dynamic molecular surface areas. J. Am. Chem. Soc. 111, 7750-7753.
110. [110] Boyd, D.B. and Lipkowitz, K.B. (1982) Molecular mechanics. The method and its underlying philosophy. J. Chem. Educ. 59, 269-273.
111. [111] Palm, K., Luthman, K., Ungell, A.-L., Strandlund, G. and Artursson, P. (1996) Correlation of drug absorption with molecular surface properties. J. Pharm. Sci. 85, 32-39.
112. [112] Petitjean, M. (1994) On the analytical calculation of van der Waals surfaces and volumes: some numerical aspects. J. Comp. Chem. 15, 507-523.
113. [113] Palm, K., Luthman, K. and Artursson, P. (1995) The relationship between dynamic molecular surface properties of highly lipophilic compounds and intestinal epithelial permeability. Pharm. Res. 12. S-297.