Coexistence of passive and carrier-mediated processes in drug transport

Nature Reviews Drug Discovery

Volumn 9, Issue 8, 2010, Pages 597-614

  Sugano, Kiyohiko ^a   Kansy, Manfred ^b   Artursson, Per ^c   Avdeef, Alex ^d   Bendels, Stefanie ^b   Di, Li ^e   Ecker, Gerhard F ^f   Faller, Bernard ^g   Fischer, Holger ^b   Gerebtzoff, Grégori ^b   Lennernaes, Hans ^c   Senner, Frank ^b  

^a Research Formulation   (United Kingdom)

^b F Hoffmann La Roche   (Switzerland)

^c UPPSALA UNIVERSITY   (Sweden)

^d PION INC   (United States)

^e Dynamics and Metabolism Department   (United States)

^f UNIVERSITY OF VIENNA   (Austria)

^g NOVARTIS PHARMA AG   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

AMOXICILLIN; AMPRENAVIR; ASIMADOLINE; CEFALEXIN; CEFIXIME; CIMETIDINE; CYCLOSPORIN; DIGOXIN; DIHYDROERGOCRYPTINE; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; ENALAPRIL; ERYTHROMYCIN; FEXOFENADINE; INDINAVIR; IVERMECTIN; KETOCONAZOLE; LEVODOPA; LISINOPRIL; LOPERAMIDE; NELFINAVIR; PACLITAXEL; RANITIDINE; RETINOIC ACID; RIFAMPICIN; RITONAVIR; SALINOMYCIN; SAQUINAVIR; UNINDEXED DRUG; VALACICLOVIR; VERAPAMIL;

AREA UNDER THE CURVE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG COMPETITION; DRUG DISPOSITION; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG EXPOSURE; DRUG METABOLISM; DRUG PENETRATION; DRUG RESEARCH; DRUG TRANSPORT; HUMAN; INTESTINE MUCOSA PERMEABILITY; LIPID BILAYER; MEMBRANE PERMEABILITY; MEMBRANE TRANSPORT; NONHUMAN; NOTE; PASSIVE TRANSPORT; PH; PRIORITY JOURNAL; TEMPERATURE DEPENDENCE; TRANSPORT KINETICS;

ANIMALS; BIOLOGICAL TRANSPORT; BIOLOGICAL TRANSPORT, ACTIVE; CELL MEMBRANE; CELL MEMBRANE PERMEABILITY; DRUG DESIGN; HUMANS; PERMEABILITY; PHARMACEUTICAL PREPARATIONS;

EID: 77955159974     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd3187     Document Type: Note

References (239)

1. Dobson, P. D. & Kell, D. B. Carrier-mediated cellularuptake of pharmaceutical drugs: an exception orthe rule? Nature Rev. Drug Discov. 7, 205-220(2008).
2. Dobson, P. D., Lanthaler, K., Oliver, S. G. & Kell, D. B. Implications of the dominant role of transportersin drug uptake by cells. Curr. Top. Med. Chem. 9,163-181 (2009).
3. Giacomini, K. M. et al. Membrane transporters in drugdevelopment. Nature Rev. Drug Discov. 9, 215-236(2010).
4. Hoegerle, M. L. & Winne, D. Drug absorption bythe rat jejunum perfused in situ. Dissociation fromthe pH-partition theory and role of microclimate-pHand unstirred layer. Naunyn SchmiedebergsArch. Pharmacol. 322, 249-255 (1983).
5. Hogben, C. A., Tocco, D. J., Brodie, B. B. &Schanker, L. S. On the mechanism of intestinalabsorption of drugs. J. Pharmacol. Exp. Ther. 125, 275-282 (1959).
6. Corti, G., Maestrelli, F., Cirri, M., Zerrouk, N. &Mura, P. Development and evaluation of an in vitromethod for prediction of human drug absorption. Eur. J. Pharm. Sci. 27, 354-362 (2006).
7. Zhu, C., Jiang, L., Chen, T. M. & Hwang, K. K. A comparative study of artificial membranepermeability assay for high throughput profiling ofdrug absorption potential. Eur. J. Med. Chem. 37,399-407 (2002).
8. Cohen, B. E. & Bangham, A. D. Diffusion of smallnonelectrolytes across liposome membranes. Nature 236, 173-174 (1972).
9. Xiang, T. X. & Anderson, B. D. Influence of chainordering on the selectivity of dipalmitoylphosphatidylcholinebilayer membranes for permeant sizeand shape. Biophys. J. 75, 2658-2671 (1998).
10. Meier, M., Blatter, X. L., Seelig, A. & Seelig, J. Interaction of verapamil with lipid membranes andP-glycoprotein: connecting thermodynamicsand membrane structure with functional activity. Biophys. J. 91, 2943-2955 (2006).
11. Seelig, A. The role of size and charge for blood-brainbarrier permeation of drugs and fatty acids. J. Mol. Neurosci. 33, 32-41 (2007).
12. Irvine, J. D. et al. MDCK (Madin-Darby canine kidney)cells: a tool for membrane permeability screening. J. Pharm. Sci. 88, 28-33 (1999).
13. Fredriksson, R., Nordstrom, K. J., Stephansson, O.,Hagglund, M. G. & Schioth, H. B. The solute carrier(SLC) complement of the human genome: phylogeneticclassification reveals four major families. FEBS Lett. 582, 3811-3816 (2008).
14. He, L., Vasiliou, K. & Nebert, D. W. Analysis andupdate of the human solute carrier (SLC) genesuperfamily. Hum. Genomics 3, 195-206 (2009).
15. Van de Waterbeemd, H. in Comprehensive MedicinalChemistry II Vol. 5 (eds Testa, B. & Van deWaterbeemd, H.) 669-697, (Elsevier Science,New York, 2006).
16. Chang, C., Ray, A. & Swaan, P. In silico strategiesfor modeling membrane transporter function. Drug Discov. Today 10, 663-671 (2005).
17. Wiese, M. & Pajeva, I. K. in ComprehensiveMedicinal Chemistry II Vol. 5 (eds Testa, B. &Van de Waterbeemd, H.) 767-794 (Elsevier Science,New York, 2006).
18. Banerjee, A., Johnston, J. S. & Swaan, P. W. inCellular Drug Delivery: Principles and Practice. Ch. 7(eds Lu, D. R. & Oie, S.) 107-128 (Humana Press,New Jersey, 2004).
19. Lee, V. H. Membrane transporters. Eur. J. Pharm. Sci. 11, S41-S50 (2000).
20. Mueller, P., Rudin, D. O., Tien, H. T. & Wescott, W. C. Reconstitution of cell membrane structure in vitro andits transformation into an excitable system. Nature194, 979-980 (1962).
21. Saparov, S. M., Antonenko, Y. N. & Pohl, P. A newmodel of weak acid permeation through membranesrevisited: does Overton still rule? Biophys. J. 90,L86-L88 (2006).
22. Walter, A. & Gutknecht, J. Monocarboxylic acidpermeation through lipid bilayer membranes. J. Membr. Biol. 77, 255-264 (1984).
23. Walter, A. & Gutknecht, J. Permeability of smallnonelectrolytes through lipid bilayer membranes. J. Membr. Biol. 90, 207-217 (1986).
24. Paul, E. C., Hochman, J. & Quaroni, A. Conditionallyimmortalized intestinal epithelial cells: novel approachfor study of differentiated enterocytes. Am. J. Physiol. 265, C266-C278 (1993).
25. Tavelin, S. et al. An improved cell culture model basedon 2/4/A1 cell monolayers for studies of intestinaldrug transport: characterization of transport routes. Pharm. Res. 20, 373-381 (2003).
26. Bermejo, M. et al. PAMPA\a drug absorptionin vitro model 7. Comparing rat in situ, Caco-2,and PAMPA permeability of fluoroquinolones. Eur. J. Pharm. Sci. 21, 429-441 (2004).
27. Neuhoff, S., Ungell, A. L., Zamora, I. & Artursson, P. pH-dependent passive and active transport of acidicdrugs across Caco-2 cell monolayers. Eur. J. Pharm. Sci. 25, 211-220 (2005).
28. Pade, V. & Stavchansky, S. Estimation of the relativecontribution of the transcellular and paracellularpathway to the transport of passively absorbed drugsin the Caco-2 cell culture model. Pharm. Res. 14,1210-1215 (1997).
29. Takanaga, H., Tamai, I. & Tsuji, A. pH-dependent andcarrier-mediated transport of salicylic acid acrossCaco-2 cells. J. Pharm. Pharmacol. 46, 567-570(1994).
30. Tsuji, A., Simanjuntak, M. T., Tamai, I. & Terasaki, T. pH-dependent intestinal transport of monocarboxylicacids: carrier-mediated and H+-cotransportmechanism versus pH-partition hypothesis. J. Pharm. Sci. 79, 1123-1124 (1990).
31. Kopplow, K., Letschert, K., Konig, J., Walter, B. &Keppler, D. Human hepatobiliary transport of organicanions analyzed by quadruple-transfected cells. Mol. Pharmacol. 68, 1031-1038 (2005).
32. Sasaki, M., Suzuki, H., Ito, K., Abe, T. & Sugiyama, Y. Transcellular transport of organic anions across adouble-transfected Madin-Darby canine kidney II cellmonolayer expressing both human organic aniontransportingpolypeptide (OATP2/SLC21A6) andmultidrug resistance-associated protein 2 (MRP2/ABCC2). J. Biol. Chem. 277, 6497-6503 (2002).
33. Lennernas, H. Human intestinal permeability. J. Pharm. Sci. 87, 403-410 (1998).
34. Lennernas, H. Intestinal permeability and itsrelevance for absorption and elimination. Xenobiotica 37, 1015-1051 (2007).
35. Lennernas, H. Modeling gastrointestinal drugabsorption requires more in vivo biopharmaceuticaldata: experience from in vivo dissolution andpermeability studies in humans. Curr. Drug Metab. 8, 645-657 (2007).
36. Collett, A., Tanianis-Hughes, J., Hallifax, D. &Warhurst, G. Predicting P-glycoprotein effects on oralabsorption: correlation of transport in Caco-2 withdrug pharmacokinetics in wild-type and mdr1a-/-micein vivo. Pharm. Res. 21, 819-826 (2004).
37. Avdeef, A. et al. Caco-2 permeability of weaklybasic drugs predicted with the double-sink PAMPApKaflux method. Eur. J. Pharm. Sci. 24, 333-349(2005).
38. Matsson, P., Pedersen, J. M., Norinder, U.,Bergstroem, C. A. & Artursson, P. Identification ofnovel specific and general inhibitors of the three majorhuman ATP-binding cassette transporters P-gp, BCRPand MRP2 among registered drugs. Pharm. Res. 26,1816-1831 (2009).
39. Kim, R. B. et al. Interrelationship between substratesand inhibitors of human CYP3A and P-glycoprotein. Pharm. Res. 16, 408-414 (1999).
40. Kansy, M., Senner, F. & Gubernator, K. Physicochemical high throughput screening:parallel artificial membrane permeation assayin the description of passive absorption processes. J. Med. Chem. 41, 1007-1010 (1998).
41. Avdeef, A., Kansy, M., Bendels, S. & Tsinman, K. Absorption- excipient-pH classification gradientmaps: sparingly soluble drugs and the pH partitionhypothesis. Eur. J. Pharm. Sci. 33, 29-41 (2008).
42. Nielsen, P. E. & Avdeef, A. PAMPA\a drugabsorption in vitro model 8. Apparent filter porosityand the unstirred water layer. Eur. J. Pharm. Sci. 22,33-41 (2004).
43. Sugano, K. in Comprehensive Medicinal Chemistry IIVol. 5 (eds Testa, B. & Van de Waterbeemd, H.)453-487 (Elsevier, Oxford, 2007).
44. Artursson, P. & Borchardt, R. T. Intestinal drugabsorption and metabolism in cell cultures: Caco-2and beyond. Pharm. Res. 14, 1655-1658 (1997).
45. Englund, G. et al. Regional levels of drug transportersalong the human intestinal tract: co-expression of ABCand SLC transporters and comparison with Caco-2cells. Eur. J. Pharm. Sci. 29, 269-277 (2006).
46. Hilgendorf, C. et al. Expression of thirty-six drugtransporter genes in human intestine, liver, kidney,and organotypic cell lines. Drug Metab. Dispos. 35,1333-1340 (2007).
47. Hubatsch, I., Ragnarsson, E. G. & Artursson, P. Determination of drug permeability and prediction ofdrug absorption in Caco-2 monolayers. Nature Protoc. 2, 2111-2119 (2007).
48. Neuhoff, S., Ungell, A.-L., Zamora, I. & Artursson, P. pH-dependent bidirectional transport of weakly basicdrugs across Caco-2 monolayers: implications fordrug-drug interactions. Pharm. Res. 20, 1141-1148(2003).
49. Pickett, S. D., McLay, I. M. & Clark, D. E. Enhancingthe hit-to-lead properties of lead optimizationlibraries. J. Chem. Inf. Comput. Sci. 40, 263-272(2000).
50. Feng, B. et al. In vitro P-glycoprotein assays to predictthe in vivo interactions of P-glycoprotein with drugs inthe central nervous system. Drug Metab. Dispos. 36,268-275 (2008).
51. Thiel-Demby, V. E. et al. Biopharmaceuticsclassification system: validation and learnings of anin vitro permeability assay. Mol. Pharm. 6, 11-18(2009).
52. Volpe, D. A. Variability in Caco-2 and MDCK cell-basedintestinal permeability assays. J. Pharm. Sci. 97,712-725 (2008).
53. Hayeshi, R. et al. Comparison of drug transportergene expression and functionality in Caco-2 cells from10 different laboratories. Eur. J. Pharm. Sci. 35,383-396 (2008).
54. Sugano, K., Takata, N., Machida, M., Saitoh, K. &Terada, K. Prediction of passive intestinal absorptionusing bio-mimetic artificial membrane permeationassay and the paracellular pathway model. Int. J. Pharm. 241, 241-251 (2002).
55. Avdeef, A. et al. Parallel artificial membranepermeability assay (PAMPA)-critical factors forbetter predictions of absorption. J. Pharm. Sci. 96, 2893-2909 (2007).
56. Galinis-Luciani, D., Nguyen, L. & Yazdanian, M. Isparallel artificial membrane permeability assaya useful tool for discovery? J. Pharm. Sci. 96,2886-2892 (2007).
57. Rautio, J., Laine, K. & Gynther, M. Enhanced braindrug delivery and targeting. Pharm. Technol. Eur. 20, 27-29, 32-33 (2008).
58. Sugano, K., Nabuchi, Y., Machida, M. & Asoh, Y. Permeation characteristics of a hydrophilic basiccompound across a bio-mimetic artificial membrane. Int. J. Pharm. 275, 271-278 (2004).
59. Takagi, M. et al. A new interpretation of salicylic acidtransport across the lipid bilayer: implications ofpH-dependent but not carrier-mediated absorptionfrom the gastrointestinal tract. J. Pharmacol. Exp. Ther. 285, 1175-1180 (1998).
60. Valko, K. & Reynolds, D. P. High-throughputphysicochemical and in vitro ADMET screening:a role in pharmaceutical profiling. Am. J. Drug Deliv. 3, 83-100 (2005).
61. Gustafsson, D. et al. The direct thrombin inhibitormelagatran and its oral prodrug H 376/95:intestinal absorption properties, biochemical andpharmacodynamic effects. Thromb. Res. 101,171-181 (2001).
62. Sugano, K. et al. Quantitative structure-intestinalpermeability relationship of benzamidine analoguethrombin inhibitor. Bioorg. Med. Chem. Lett. 10,1939-1942 (2000).
63. Fischer, H., Kansy, M., Avdeef, A. & Senner, F. Permeation of permanently positive chargedmolecules through artificial membranes\influenceof physico-chemical properties. Eur. J. Pharm. Sci. 31, 32-42 (2007).
64. Ruifrok, P. G. & Meijer, D. K. Transport of organicions through lipid bilayers. Naunyn SchmiedebergsArch. Pharmacol. 316, 266-272 (1981).
65. Poirier, A. et al. Design, data analysis and simulationof in vitro drug transport kinetic experiments using amechanistic in vitro model. Drug Metab. Dispos. 36,2434-2444 (2008).
66. Lei, Y. D., Wania, F., Shiu, W. Y. & Boocock, D. G. B. HPLC-based method for estimating the temperaturedependence of n-Octanol-water partition coefficients. J. Chem. Eng. Data 45, 738-742 (2000).
67. Tanaka, M., Fukuda, H. & Nagai, T. Permeationof a drug through a model membrane consisting ofmillipore filter with oil. Chem. Pharm. Bull. 26, 9-13(1978).
68. Raeissi, S. D., Li, J. & Hidalgo, I. J. The role of anα-amino group on H+-dependent transepithelialtransport of cephalosporins in Caco-2 cells. J. Pharm. Pharmacol. 51, 35-40 (1999).
69. Takacs-Novak, K., Box, K. J. & Avdeef, A. Potentiometric pKa determination of water-insolublecompounds: validation study in methanol/watermixtures. Int. J. Pharm. 151, 235-248 (1997).
70. Said, H. M., Blair, J. A., Lucas, M. L. & Hilburn, M. E. Intestinal surface acid microclimate in vitro andin vivo in the rat. J. Lab. Clin. Med. 107, 420-424(1986).
71. Xiang, T. X. & Anderson, B. D. Substituentcontributions to the transport of substituted p-toluicacids across lipid bilayer membranes. J. Pharm. Sci. 83, 1511-1518 (1994).
72. Cohen, B. E. Permeability of liposomes tononelectrolytes. II. Effect of nystatin and gramicidin A. J. Membr. Biol. 20, 235-268 (1975).
73. Cao, Y., Xiang, T.-X. & Anderson, B. D. Development ofstructure-lipid bilayer permeability relationships forpeptide-like small organic molecules. Mol. Pharm. 5,371-388 (2008).
74. Camenisch, G., Alsenz, J., van de Waterbeemd, H. & Folkers, G. Estimation of permeability by passivediffusion through Caco-2 cell monolayers usingthe drugs' lipophilicity and molecular weight. Eur. J. Pharm. Sci. 6, 313-319 (1998).
75. Johnson, T. W., Dress, K. R. & Edwards, M. Using the Golden Triangle to optimize clearanceand oral absorption. Bioorg. Med. Chem. Lett. 19,5560-5564 (2009).
76. Linnankoski, J., Ranta, V.-P., Yliperttula, M. & Urtti, A. Passive oral drug absorption can be predicted morereliably by experimental than computational models\fact or myth. Eur. J. Pharm. Sci. 34, 129-139(2008).
77. Lombardo, F., Obach, R. S., Shalaeva, M. Y. & Gao, F. Prediction of volume of distribution values in humansfor neutral and basic drugs using physicochemicalmeasurements and plasma protein binding data. J. Med. Chem. 45, 2867-2876 (2002).
78. Martin, Y. C. A practitioner's perspective of the roleof quantitative structure-activity analysis inmedicinal chemistry. J. Med. Chem. 24, 229-237(1981).
79. Obach, R. S., Lombardo, F. & Waters, N. J. Trendanalysis of a database of intravenous pharmacokineticparameters in humans for 670 drug compounds. Drug Metab. Dispos. 36, 1385-1405 (2008).
80. Obata, K. et al. Prediction of oral drug absorptionin humans by theoretical passive absorption model. Int. J. Pharm. 293, 183-192 (2005).
81. Rodgers, T. & Rowland, M. Physiologically basedpharmacokinetic modelling 2: predicting the tissuedistribution of acids, very weak bases, neutrals andzwitterions. J. Pharm. Sci. 95, 1238-1257 (2006).
82. Rodgers, T. & Rowland, M. Mechanistic approaches tovolume of distribution predictions: understanding theprocesses. Pharm. Res. 24, 918-933 (2007).
83. Veber, D. F. et al. Molecular properties that influencethe oral bioavailability of drug candidates. J. Med. Chem. 45, 2615-2623 (2002).
84. Winiwarter, S. et al. Correlation of human jejunalpermeability (in vivo) of drugs with experimentally andtheoretically derived parameters. A multivariate dataanalysis approach. J. Med. Chem. 41, 4939-4949(1998).
85. Reynolds, D. P., Lanevskij, K., Japertas, P.,Didziapetris, R. & Petrauskas, A. Ionization-specificanalysis of human intestinal absorption. J. Pharm. Sci. 98, 4039-4054 (2009).
86. Fischer, H., Gottschlich, R. & Seelig, A. Blood-brainbarrier permeation: molecular parameters governingpassive diffusion. J. Membr. Biol. 165, 201-211(1998).
87. Gratton, J. A., Abraham, M. H., Bradbury, M. W. &Chadha, H. S. Molecular factors influencing drugtransfer across the blood-brain barrier. J. Pharm. Pharmacol. 49, 1211-1216 (1997).
88. Hou, T. J., Zhang, W., Xia, K., Qiao, X. B. & Xu, X. J. ADME evaluation in drug discovery. 5. Correlation ofCaco-2 permeation with simple molecular properties. J. Chem. Inf. Comput. Sci. 44, 1585-1600 (2004).
89. Palm, K. et al. Evaluation of dynamic polar molecularsurface area as predictor of drug absorption:comparison with other computational and experimentalpredictors. J. Med. Chem. 41, 5382-5392 (1998).
90. Zhao, Y. et al. Evaluation of human intestinalabsorption data and subsequent derivation of aquantitative structure-activity relationship (QSAR)with the Abraham descriptors. J. Pharm. Sci. 90,749-784 (2001).
91. Avdeef, A. in Absorption and Drug Development:Solubility, Permeability and Charge State 1-312(Wiley-Interscience, Hoboken, New Jersey, 2003).
92. Camenisch, G., Folkers, G. & van de Waterbeemd, H. Comparison of passive drug transport through Caco-2cells and artificial membranes. Int. J. Pharm. 147,61-70 (1997).
93. Dagenais, C., Avdeef, A., Tsinman, O., Dudley, A. &Beliveau, R. P-glycoprotein deficient mouse in situblood-brain barrier permeability and its predictionusing an in combo PAMPA model. Eur. J. Pharm. Sci. 38, 121-137 (2009).
94. Di, L., Kerns, E. H., Bezar, I. F., Petusky, S. L. &Huang, Y. Comparison of blood-brain barrierpermeability assays: in situ brain perfusion,MDR1-MDCKII and PAMPA-BBB. J. Pharm. Sci. 98, 1980-1991 (2009).
95. Di, L., Kerns, E. H., Fan, K., McConnell, O. J. &Carter, G. T. High throughput artificial membranepermeability assay for blood-brain barrier. Eur. J. Med. Chem. 38, 223-232 (2003).
96. Flaten, G. E., Dhanikula, A. B., Luthman, K. &Brandl, M. Drug permeability across a phospholipidvesicle based barrier: a novel approach for studyingpassive diffusion. Eur. J. Pharm. Sci. 27, 80-90 (2006).
97. Kerns, E. H. et al. Combined application of parallelartificial membrane permeability assay and Caco-2permeability assays in drug discovery. J. Pharm. Sci. 93, 1440-1453 (2004).
98. Kwon, J.-H. & Escher, B. I. A modified parallel artificialmembrane permeability assay for evaluating thebioconcentration of highly hydrophobic chemicals infish. Environ. Sci. Technol. 42, 1787-1793 (2008).
99. Li, C. et al. Correlation between PAMPA permeabilityand cellular activities of hepatitis C virus proteaseinhibitors. Biochem. Pharmacol. 75, 1186-1197(2008).
100. Matsson, P. et al. Exploring the role of different drugtransport routes in permeability screening. J. Med. Chem. 48, 604-613 (2005).
101. Miret, S., Abrahamse, L. & de Groene, E. M. Comparison of in vitro models for the prediction ofcompound absorption across the human intestinalmucosa. J. Biomol. Screen. 9, 598-606 (2004).
102. Ottaviani, G., Martel, S. & Carrupt, P.-A. Parallelartificial membrane permeability assay: a newmembrane for the fast prediction of passive humanskin permeability. J. Med. Chem. 49, 3948-3954(2006).
103. Saitoh, R. et al. Correction of permeability withpore radius of tight junctions in Caco-2 monolayersimproves the prediction of the dose fraction ofhydrophilic drugs absorbed by humans. Pharm. Res. 21, 749-755 (2004).
104. Sugano, K., Hamada, H., Machida, M. & Ushio, H. High throuput prediction of oral absorption:improvement of the composition of the lipid solutionused in parallel artificial membrane permeation assay. J. Biomol. Screen. 6, 189-196 (2001).
105. Sugano, K., Nabuchi, Y., Machida, M. & Aso, Y. Prediction of human intestinal permeability usingartificial membrane permeability. Int. J. Pharm. 257, 245-251 (2003).
106. Wohnsland, F. & Faller, B. High-throughputpermeability pH profile and high-throughput alkane/water log P with artificial membranes. J. Med. Chem. 44, 923-930 (2001).
107. Avdeef, A. The rise of PAMPA. Expert Opin. DrugMetab. Toxicol. 1, 325-342 (2005).
108. Beigi, F. et al. Immobilized liposome andbiomembrane partitioning chromatography ofdrugs for prediction of drug transport. Int. J. Pharm. 164, 129-137 (1998).
109. Danelian, E. et al. SPR biosensor studies of the directinteraction between 27 drugs and a liposome surface:correlation with fraction absorbed in humans. J. Med. Chem. 43, 2083-2086 (2000).
110. Loidl-Stahlhofen, A., Eckert, A., Hartmann, T. &Schottner, M. Solid-supported lipid membranes asa tool for determination of membrane affinity:high-throughput screening of a physicochemicalparameter. J. Pharm. Sci. 90, 599-606 (2001).
111. Pidgeon, C. et al. IAM chromatography: an in vitroscreen for predicting drug membrane permeability. J. Med. Chem. 38, 590-594 (1995).
112. Ano, R. et al. Relationships between structure andhigh-throughput screening permeability of peptidederivatives and related compounds with artificialmembranes: application to prediction of Caco-2 cellpermeability. Bioorg. Med. Chem. 12, 257-264(2004).
113. Fujikawa, M., Nakao, K., Shimizu, R. & Akamatsu, M. QSAR study on permeability of hydrophobiccompounds with artificial membranes. Bioorg. Med. Chem. 15, 3756-3767 (2007).
114. Kansy, M. et al. in Pharmacokinetic Optimization inDrug Research: Biological, Physicochemical andComputational Strategies (eds Testa, B., Van deWaterbeemd, H., Folkers, G. & Guy, R.) 447-464(Wiley-VCH, Zurich, 2001).
115. Kubinyi, H. Drug partitioning: relationships betweenforward and reverse rate constants and partitioncoefficient. J. Pharm. Sci. 67, 262-263 (1978).
116. Kubinyi, H. Lipophilicity and drug activity. Prog. DrugRes. 23, 97-198 (1979).
117. Wenlock, M. C., Austin, R. P., Barton, P., Davis, A. M. & Leeson, P. D. A comparison of physiochemicalproperty profiles of development and marketed oraldrugs. J. Med. Chem. 46, 1250-1256 (2003).
118. Balimane, P. V. et al. Peptide transporter substrateidentification during permeability screening in drugdiscovery: comparison of transfected MDCK-hPepT1cells to Caco-2 cells. Arch. Pharm. Res. 30, 507-518(2007).
119. Balimane, P. V. et al. A novel high-throughputautomated chip-based nanoelectrospray tandem massspectrometric method for PAMPA sample analysis. J. Pharm. Biomed. Anal. 39, 8-16 (2005).
120. Di, L. & Kerns, E. H. Profiling drug-like propertiesin discovery research. Curr. Opin. Chem. Biol. 7,402-408 (2003).
121. Sugano, K., Obata, K., Saitoh, R., Higashida, A. &Hamada, H. in Pharmacokinetic Profiling in DrugResearch (eds Testa, B., Krämer, S., Wunderli-Allenspach, H. & Folkers, G.) 441-458 (Wiley-VCH,Zurich, 2006).
122. Masungi, C. et al. Parallel artificial membranepermeability assay (PAMPA) combined with a 10-daymultiscreen Caco-2 cell culture as a tool for assessingnew drug candidates. Pharmazie 63, 194-199(2008).
123. Tavelin, S. et al. Prediction of the oral absorption oflow-permeability drugs using small intestine-like2/4/A1 cell. monolayers. Pharm. Res. 20, 397-405(2003).
124. Lagas, J. S., Vlaming, M. L. & Schinkel, A. H. Pharmacokinetic assessment of multiple ATP-bindingcassette transporters: the power of combinationknockout mice. Mol. Interv. 9, 136-145 (2009).
125. van de Steeg, E. et al. Methotrexate pharmacokineticsin transgenic mice with liver-specific expression ofhuman organic anion-transporting polypeptide 1B1(SLCO1B1). Drug Metab. Dispos. 37, 277-281(2009).
126. Chen, C., Liu, X. & Smith, B. J. Utility of Mdr1-genedeficient mice in assessing the impact of P-glycoproteinon pharmacokinetics and pharmacodynamics in drugdiscovery and development. Curr. Drug Metab. 4,272-291 (2003).
127. Chiou, W. L., Chung, S. M. & Wu, T. C. Apparent lackof effect of P-glycoprotein on the gastrointestinalabsorption of a substrate, tacrolimus, in normal mice. Pharm. Res. 17, 205-208 (2000).
128. del Amo, E. M., Heikkinen, A. T. & Moenkkoenen, J. In vitro-in vivo correlation in P-glycoprotein mediatedtransport in intestinal absorption. Eur. J. Pharm. Sci. 36, 200-211 (2009).
129. Kato, Y. et al. Investigation of the role of oligopeptidetransporter PEPT1 and sodium/glucose cotransporterSGLT1 in intestinal absorption of their substratesusing small GTP-binding protein Rab8-null mice. Drug Metab. Dispos. 37, 602-607 (2009).
130. Hironaka, T., Itokawa, S., Ogawara, K., Higaki, K. & Kimura, T. Quantitative evaluation of PEPT1contribution to oral absorption of cephalexin in rats. Pharm. Res. 26, 40-50 (2009).
131. Johnson, W. W. P-glycoprotein-mediated efflux asa major factor in the variance of absorption anddistribution of drugs: modulation of chemotherapyresistance. Methods Find. Exp. Clin. Pharmacol. 24,501-514 (2002).
132. Brandsch, M., Knutter, I. & Bosse-Doenecke, E. Pharmaceutical and pharmacological importanceof peptide transporters. J. Pharm. Pharmacol. 60,543-585 (2008).
133. Knutter, I. et al. Transport of angiotensin-convertingenzyme inhibitors by H+/peptide transportersrevisited. J. Pharmacol. Exp. Ther. 327, 432-441(2008).
134. Brandsch, M. Transport of drugs by proton-coupledpeptide transporters: pearls and pitfalls. Expert Opin. Drug Metab. Toxicol. 5, 887-905 (2009).
135. Schoenmakers, R. G., Stehouwer, M. C. & Tukker, J. J. Structure-transport relationship for the intestinalsmall-peptide carrier: is the carbonyl group of thepeptide bond relevant for transport? Pharm. Res. 16, 62-68 (1999).
136. Cao, X. et al. Why is it challenging to predict intestinaldrug absorption and oral bioavailability in humanusing rat model. Pharm. Res. 23, 1675-1686 (2006).
137. Chiou, W. L., Chung, S. M., Wu, T. C. & Ma, C. A comprehensive account on the role of effluxtransporters in the gastrointestinal absorption of 13commonly used substrate drugs in humans. Int. J. Clin. Pharmacol. Ther. 39, 93-101 (2001).
138. Kwon, H., Lionberger, R. A. & Yu, L. X. Impact ofP-glycoprotein- mediated intestinal efflux kineticson oral bioavailability of P-glycoprotein substrates. Mol. Pharm. 1, 455-465 (2004).
139. Amidon, G. L., Lennernas, H., Shah, V. P. &Crison, J. R. A theoretical basis for a biopharmaceuticdrug classification: the correlation of in vitro drugproduct dissolution and in vivo bioavailability. Pharm. Res. 12, 413-420 (1995).
140. Lin, J. H. & Yamazaki, M. Role of P-glycoproteinin pharmacokinetics: clinical implications. Clin. Pharmacokinet. 42, 59-98 (2003).
141. Cao, X. et al. Permeability dominates in vivo intestinalabsorption of P-gp substrate with high solubilityand high permeability. Mol. Pharm. 2, 329-340(2005).
142. Doppenschmitt, S., Spahn-Langguth, H., Regardh, C. G. & Langguth, P. Role of P-glycoprotein-mediatedsecretion in absorptive drug permeability:an approach using passive membrane permeabilityand affinity to P-glycoprotein. J. Pharm. Sci. 88,1067-1072 (1999).
143. Lentz, K. A., Polli, J. W., Wring, S. A., Humphreys, J. E. & Polli, J. E. Influence of passive permeability onapparent P-glycoprotein kinetics. Pharm. Res. 17,1456-1460 (2000).
144. Varma, M. V., Sateesh, K. & Panchagnula, R. Functional role of P-glycoprotein in limiting intestinalabsorption of drugs: contribution of passivepermeability to P-glycoprotein mediated effluxtransport. Mol. Pharm. 2, 12-21 (2005).
145. von Richter, O. et al. A novel screening strategy toidentify ABCB1 substrates and inhibitors. NaunynSchmiedebergs Arch. Pharmacol. 379, 11-26 (2009).
146. Faller, B. in Hit and Lead Profiling. Identification andOptimization of Drug-like Molecules. Methods andPrinciples in Medicinal Chemistry Vol. 43 (eds Faller,B. & Laszlo, U.) (Wiley VCH, Weinheim 2009).
147. Sun, H. & Pang, K. S. Permeability, transport, andmetabolism of solutes in Caco-2 cell monolayers:a theoretical study. Drug Metab. Dispos. 36,102-123 (2008).
148. Eytan, G. D. Mechanism of multidrug resistance inrelation to passive membrane permeation. Biomed. Pharmacother. 59, 90-97 (2005).
149. Wu, C.-Y. & Benet, L. Z. Predicting drug disposition viaapplication of BCS: transport/absorption/eliminationinterplay and development of a biopharmaceuticsdrug disposition classification system. Pharm. Res. 22, 11-23 (2005).
150. Fenner, K. S. et al. Drug-drug interactions mediatedthrough P-glycoprotein: clinical relevance andin vitro-in vivo correlation using digoxin as a probedrug. Clin. Pharmacol. Ther. 85, 173-181 (2009).
151. Oh, D.-M., Curl, R. L., Yong, C.-S. & Amidon, G. L. Effect of micronization on the extent of drugabsorption from suspensions in humans. Arch. Pharm. Res. 18, 427-433 (1995).
152. Shaw, T. R. & Carless, J. E. Effect of particle size onthe absorption of digoxin. Eur. J. Clin. Pharmacol. 7, 269-273 (1974).
153. Yu, L. X. An integrated model for determining causesof poor oral drug absorption. Pharm. Res. 16,1883-1887 (1999).
154. Ogihara, T. et al. What kinds of substrates showP-glycoprotein-dependent intestinal absorption?Comparison of verapamil with vinblastine. Drug Metab. Pharmacokinet. 21, 238-244 (2006).
155. Nagahara, N., Tavelin, S. & Artursson, P. Contributionof the paracellular route to the pH-dependentepithelial permeability to cationic drugs. J. Pharm. Sci. 93, 2972-2984 (2004).
156. Lafforgue, G. et al. Oral absorption of ampicillin:role of paracellular route vs. PepT1 transporter. Fund. Clin. Pharmacol. 22, 189-201 (2008).
157. Linnankoski, J. et al. Paracellular porosity and poresize of the human intestinal epithelium in tissue andcell culture models. J. Pharm. Sci. 99 (Suppl. 4),2166-2175 (2010).
158. Eytan, G. D., Regev, R., Oren, G. & Assaraf, Y. G. The role of passive transbilayer drug movement inmultidrug resistance and its modulation. J. Biol. Chem. 271, 12897-12902 (1996).
159. Fagerholm, U. The role of permeability in drugADME/PK, interactions and toxicity\presentationof a permeability-based classification system (PCS)for prediction of ADME/PK in humans. Pharm. Res. 25, 625-638 (2008).
160. Kohl, C. Transporters\the view from industry. Chem. Biodivers. 6, 1988-1999 (2009).
161. Scherrmann, J. M. Transporters in absorption,distribution, and elimination. Chem. Biodivers. 6,1933-1942 (2009).
162. Shugarts, S. & Benet, L. Z. The role of transportersin the pharmacokinetics of orally administered drugs. Pharm. Res. 26, 2039-2054 (2009).
163. Petri, N., Tannergren, C., Rungstad, D. &Lennernaes, H. Transport characteristics offexofenadine in the Caco-2 cell model. Pharm. Res. 21, 1398-1404 (2004).
164. Cvetkovic, M., Leake, B., Fromm, M. F., Wilkinson, G. R. & Kim, R. B. OATP and P-glycoprotein transportersmediate the cellular uptake and excretion offexofenadine. Drug Metab. Dispos. 27, 866-871(1999).
165. Tannergren, C., Knutson, T., Knutson, L. &Lennernas, H. The effect of ketoconazole on thein vivo intestinal permeability of fexofenadine using aregional perfusion technique. Br. J. Clin. Pharmacol. 55, 182-190 (2003).
166. Glaeser, H. et al. Intestinal drug transporterexpression and the impact of grapefruit juice inhumans. Clin. Pharmacol. Ther. 81, 362-370 (2007).
167. Russel, T., Stoltz, M. & Weir, S. Pharmacokinetics,pharmacodynamics, and tolerance of single-andmultiple-dose fexofenadine hydrochloride in healthymale volunteers. Clin. Pharmacol. Ther. 64, 612-621(1998).
168. Lappin, G. et al. Pharmacokinetics of fexofenadine:evaluation of a microdose and assessment of absoluteoral bioavailability. Eur. J. Pharm. Sci. 40, 125-131(2010).
169. Korjamo, T., Kemilainen, H., Heikkinen, A. T. &Monkkonen, J. Decrease in intracellular concentrationcauses the shift in Km value of efflux pump substrates. Drug Metab. Dispos. 35, 1574-1579 (2007).
170. Tachibana, T. et al. Model analysis of theconcentration-dependent permeability of P-gpsubstrates. Pharm. Res. 27, 442-446 (2010).
171. Trotter, P. J. & Storch, J. Fatty acid uptake andmetabolism in a human intestinal cell line (Caco-2):comparison of apical and basolateral incubation. J. Lipid Res. 32, 293-304 (1991).
172. Troutman, M. D. & Thakker, D. R. Novel experimentalparameters to quantify the modulation of absorptiveand secretory transport of compounds byP-glycoprotein in cell culture models of intestinalepithelium. Pharm. Res. 20, 1210-1224 (2003).
173. Troutman, M. D. & Thakker, D. R. Efflux ratiocannot assess P-glycoprotein-mediated attenuationof absorptive transport: asymmetric effect ofP-glycoprotein on absorptive and secretory transportacross Caco-2 cell monolayers. Pharm. Res. 20,1200-1209 (2003).
174. Bailey, D. G., Dresser, G. K., Leake, B. F. & Kim, R. B. Naringin is a major and selective clinical inhibitorof organic anion-transporting polypeptide 1A2(OATP1A2) in grapefruit juice. Clin. Pharmacol. Ther. 81, 495-502 (2007).
175. Yasui-Furukori, N., Uno, T., Sugawara, K. & Tateishi, T. Different effects of three transporting inhibitors,verapamil, cimetidine, and probenecid, onfexofenadine pharmacokinetics. Clin. Pharmacol. Ther. 77, 17-23 (2005).
176. Kikuchi, A., Nozawa, T., Wakasawa, T., Maeda, T. &Tamai, I. Transporter-mediated intestinal absorption offexofenadine in rats. Drug Metab. Pharmacokinet. 21,308-314 (2006).
177. Tannergren, C. et al. Multiple transport mechanismsinvolved in the intestinal absorption and first-passextraction of fexofenadine. Clin. Pharmacol. Ther. 74,423-436 (2003).
178. Matsushima, S., Maeda, K., Ishiguro, N., Igarashi, T. & Sugiyama, Y. Investigation of the inhibitory effectsof various drugs on the hepatic uptake of fexofenadinein humans. Drug Metab. Dispos. 36, 663-669(2008).
179. Swift, B., Tian, X. & Brouwer, K. L. Integration ofpreclinical and clinical data with pharmacokineticmodeling and simulation to evaluate fexofenadine asa probe for hepatobiliary transport function. Pharm. Res. 26, 1942-1951 (2009).
180. Matsushima, S. et al. The inhibition of humanmultidrug and toxin extrusion 1 is involved inthe drug-drug interaction caused by cimetidine. Drug Metab. Dispos. 37, 555-559 (2009).
181. Grahnen, A. Cimetidine bioavailability and variablerenal clearance. Eur. J. Clin. Pharmacol. 27, 623-624(1984).
182. Grahnen, A., Jameson, S., Loof, L., Tyllstrom, J. &Lindstrom, B. Pharmacokinetics of cimetidine inadvanced cirrhosis. Eur. J. Clin. Pharmacol. 26,347-355 (1984).
183. Grahnen, A., Von Bahr, C., Lindstroem, B. & Rosen, A. Bioavailability and pharmacokinetics of cimetidine. Eur. J. Clin. Pharmacol. 16, 335-340 (1979).
184. Collett, A., Higgs, N. B., Sims, E., Rowland, M. &Warhurst, G. Modulation of the permeability of H2receptor antagonists cimetidine and ranitidine byP-glycoprotein in rat intestine and the human coloniccell line Caco-2. J. Pharmacol. Exp. Ther. 288,171-178 (1999).
185. Sun, D. et al. Comparison of human duodenum andCaco-2 gene expression profiles for 12,000 genesequences tags and correlation with permeabilityof 26 drugs. Pharm. Res. 19, 1400-1416 (2002).
186. Sun, W., Wu, R. R., van Poelje, P. D. & Erion, M. D. Isolation of a family of organic anion transportersfrom human liver and kidney. Biochem. Biophys. Res. Commun. 283, 417-422 (2001).
187. Takamatsu, N. et al. Human jejunal permeabilityof two polar drugs: cimetidine and ranitidine. Pharm. Res. 18, 742-744 (2001).
188. Jantratid, E. et al. Biowaiver monographs forimmediate release solid oral dosage forms: cimetidine. J. Pharm. Sci. 95, 974-984 (2006).
189. Christians, U., Jacobsen, W., Benet, L. Z. & Lampen, A. Mechanisms of clinically relevant drug interactionsassociated with tacrolimus. Clin. Pharmacokinet. 41,813-851 (2002).
190. Floren, L. C. et al. Tacrolimus oral bioavailabilitydoubles with coadministration of ketoconazole. Clin. Pharmacol. Ther. 62, 41-49 (1997).
191. Fricker, G., Drewe, J., Huwyler, J., Gutmann, H. &Beglinger, C. Relevance of P-glycoprotein for the enteralabsorption of cyclosporin A: in vitro-in vivo correlation. Br. J. Pharmacol. 118, 1841-1847 (1996).
192. Glavinas, H., Krajcsi, P., Cserepes, J. & Sarkadi, B. The role of ABC transporters in drug resistance,metabolism, and toxicity. Curr. Drug Deliv. 1, 27-42(2004).
193. Kruijtzer, C. M., Beijnen, J. H. & Schellens, J. H. Improvement of oral drug treatment by temporaryinhibition of drug transporters and/or cytochromeP450 in the gastrointestinal tract and liver:an overview. Oncologist 7, 516-530 (2002).
194. Kunta, J. R. & Sinko, P. J. Intestinal drug transporters:in vivo function and clinical importance. Curr. DrugMetab. 5, 109-124 (2004).
195. Lown, K. S. et al. Role of intestinal P-glycoprotein(mdr1) in interpatient variation in the oralbioavailability of cyclosporine. Clin. Pharmacol. Ther. 62, 248-260 (1997).
196. Benet, L. Z., Cummins, C. L. & Wu, C. Y. Unmaskingthe dynamic interplay between efflux transporters andmetabolic enzymes. Int. J. Pharm. 277, 3-9 (2004).
197. Ito, K., Kusuhara, H. & Sugiyama, Y. Effects ofintestinal CYP3A4 and P-glycoprotein on oral drugabsorption\theoretical approach. Pharm. Res. 16,225-231 (1999).
198. Bardelmeijer, H. A. et al. Entrapment by CremophorEL decreases the absorption of paclitaxel from thegut. Cancer Chemother. Pharmacol. 49, 119-125(2002).
199. Stephens, R. H. et al. Resolution of P-glycoprotein andnon-P-glycoprotein effects on drug permeability usingintestinal tissues from mdr1a-/-mice. Br. J. Pharmacol. 135, 2038-2046 (2002).
200. Peltier, S., Oger, J. M., Lagarce, F., Couet, W. &Benoit, J. P. Enhanced oral paclitaxel bioavailabilityafter administration of paclitaxel-loaded lipidnanocapsules. Pharm. Res. 23, 1243-1250 (2006).
201. Walle, U. K. & Walle, T. Taxol transport by humanintestinal epithelial Caco-2 cells. Drug Metab. Dispos. 26, 343-346 (1998).
202. Sandstrom, M., Simonsen, L. E., Freijs, A. &Karlsson, M. O. The pharmacokinetics of epirubicinand docetaxel in combination in rats. CancerChemother. Pharmacol. 44, 469-474 (1999).
203. Strum, W. B. A pH-dependent, carrier-mediatedtransport system for the folate analog, amethopterin,in rat jejunum. J. Pharmacol. Exp. Ther. 203, 640-645(1977).
204. Yokooji, T., Mori, N. & Murakami, T. Site-specificcontribution of proton-coupled folate transporter/haem carrier protein 1 in the intestinal absorptionof methotrexate in rats. J. Pharm. Pharmacol. 61,911-918 (2009).
205. Lennernas, H. et al. The effect of l-leucine on theabsorption of levodopa, studied by regional jejunalperfusion in man. Br. J. Clin. Pharmacol. 35,243-250 (1993).
206. Biegel, A. et al. Three-dimensional quantitativestructure-activity relationship analyses of b-lactamantibiotics and tripeptides as substrates of themammalian H+/peptide cotransporter PEPT1. J. Med. Chem. 48, 4410-4419 (2005).
207. Tannergren, C., Bergendal, A., Lennernas, H. & Abrahamsson, B. Toward an increased understandingof the barriers to colonic drug absorption in humans:implications for early controlled release candidateassessment. Mol. Pharm. 6, 60-73 (2009).
208. Skold, C. et al. Presentation of a structurally diverseand commercially available drug data set forcorrelation and benchmarking studies. J. Med. Chem. 49, 6660-6671 (2006).
209. Adachi, Y., Suzuki, H. & Sugiyama, Y. Comparativestudies on in vitro methods for evaluating in vivofunction of MDR1 P-glycoprotein. Pharm. Res. 18,1660-1668 (2001).
210. Shitara, Y., Sato, H. & Sugiyama, Y. Evaluation ofdrug-drug interaction in the hepatobiliary and renaltransport of drugs. Annu. Rev. Pharmacol. Toxicol. 45, 689-723 (2005).
211. Maeda, K., Suzuki, H. & Sugiyama, Y. Hepatictransport. Methods Princ. Med. Chem. 40, 277-332(2009).
212. Hosea, N. A. et al. Prediction of humanpharmacokinetics from preclinical information:comparative accuracy of quantitative predictionapproaches. J. Clin. Pharmacol. 49, 513-533 (2009).
213. Seelig, A. How does P-glycoprotein recognize itssubstrates? Int. J. Clin. Pharmacol. Ther. 36, 50-54(1998).
214. Seelig, A. & Landwojtowicz, E. Structure-activityrelationship of P-glycoprotein substrates andmodifiers. Eur. J. Pharm. Sci. 12, 31-40 (2000).
215. Maher Doan, K. M. et al. Passive permeability andP-glycoprotein-mediated efflux differentiate centralnervous system (CNS) and non-CNS marketed drugs. J. Pharmacol. Exp. Ther. 303, 1029-1037 (2002).
216. Adachi, Y., Suzuki, H. & Sugiyama, Y. Quantitativeevaluation of the function of small intestinalP-glycoprotein: comparative studies between in situand in vitro. Pharm. Res. 20, 1163-1169 (2003).
217. Poulin, P. & Theil, F. P. A priori prediction oftissue:plasma partition coefficients of drugsto facilitate the use of physiologically- basedpharmacokinetic models in drug discovery. J. Pharm. Sci. 89, 16-35 (2000).
218. Schinkel, A. H. et al. Disruption of the mouse mdr1aP-glycoprotein gene leads to a deficiency in theblood-brain barrier and to increased sensitivity todrugs. Cell 77, 491-502 (1994).
219. Shitara, Y., Horie, T. & Sugiyama, Y. Transporters as adeterminant of drug clearance and tissue distribution. Eur. J. Pharm. Sci. 27, 425-446 (2006).
220. Ieiri, I., Higuchi, S. & Sugiyama, Y. Geneticpolymorphisms of uptake (OATP1B1, 1B3) and efflux(MRP2, BCRP) transporters: implications for interindividualdifferences in the pharmacokinetics andpharmacodynamics of statins and other clinicallyrelevant drugs. Expert Opin. Drug Metab. Toxicol. 5,703-729 (2009).
221. Chou, C., McLachlan, A. J. & Rowland, M. Membrane permeability and lipophilicity in theisolated perfused rat liver: 5-ethyl barbituric acid andother compounds. J. Pharmacol. Exp. Ther. 275,933-940 (1995).
222. Huang, L. et al. Relationship between passivepermeability, efflux, and predictability of clearancefrom in vitro metabolic intrinsic clearance. Drug Metab. Dispos. 38, 223-231 (2009).
223. Fagerholm, U. Prediction of human pharmacokinetics\renal metabolic and excretion clearance. J. Pharm. Pharmacol. 59, 1463-1471 (2007).
224. Abrahamsson, B. & Lennernaes, H. Application of thebiopharmaceutics classification system now and inthe future. Methods Princ. Med. Chem. 40, 523-558(2009).
225. Balimane, P. V., Han, Y. H. & Chong, S. Currentindustrial practices of assessing permeability andP-glycoprotein interaction. AAPS J. 8, E1-13(2006).
226. Ganapathy, M. E., Huang, W., Wang, H., Ganapathy, V. & Leibach, F. H. Valacyclovir: a substrate for theintestinal and renal peptide transporters PEPT1and PEPT2. Biochem. Biophys. Res. Commun. 246,470-475 (1998).
227. Han, H. et al. 5′-amino acid esters of antiviralnucleosides, acyclovir, and AZT are absorbed by theintestinal PEPT1 peptide transporter. Pharm. Res. 15, 1154-1159 (1998).
228. Mealey, K. L., Bentjen, S. A., Gay, J. M. &Cantor, G. H. Ivermectin sensitivity in collies isassociated with a deletion mutation of the mdr1gene. Pharmacogenetics 11, 727-733 (2001).
229. Testa, B. in Comprehensive Medicinal Chemistry IIVol. 5 (eds. Testa, B. & van de Waterbeemd, H.)1009-1041 (Elsevier Science, New York, 2006).
230. Watanabe, T., Kusuhara, H., Maeda, K., Shitara, Y. & Sugiyama, Y. Physiologically basedpharmacokinetic modeling to predict transportermediatedclearance and distribution of pravastatin inhumans. J. Pharmacol. Exp. Ther. 328, 652-662(2009).
231. Winterhalter, M. Black lipid membranes. Curr. Opin. Colloid Interface Sci. 5, 250-255 (2000).
232. Balon, K., Riebesehl, B. U. & Muller, B. W. Drugliposome partitioning as a tool for the predictionof human passive intestinal absorption. Pharm. Res. 16, 882-888 (1999).
233. Harrigan, P. R., Wong, K. F., Redelmeier, T. E.,Wheeler, J. J. & Cullis, P. R. Accumulation ofdoxorubicin and other lipophilic amines into largeunilamellar vesicles in response to transmembrane pHgradients. Biochim. Biophys. Acta 1149, 329-338(1993).
234. Yan, E. C. & Eisenthal, K. B. Effect of cholesterolon molecular transport of organic cations acrossliposome bilayers probed by second harmonicgeneration. Biophys. J. 79, 898-903 (2000).
235. Xiang, T. X. & Anderson, B. D. The relationshipbetween permeant size and permeability in lipidbilayer membranes. J. Membr. Biol. 140, 111-122(1994).
236. Ahlin, G. et al. Structural requirements for druginhibition of the liver specific human organic cationtransport protein. J. Med. Chem. 51, 5932-5942(2008).
237. Pedersen, J. M. et al. Prediction and identificationof drug interactions with the human ATP-bindingcassette transporter multidrug-resistance associatedprotein 2 (MRP2; ABCC2). J. Med. Chem. 51,3275-3287 (2008).
238. Palm, K., Stenberg, P., Luthman, K. & Artursson, P. Polar molecular surface properties predict theintestinal absorption of drugs in humans. Pharm. Res. 14, 568-571 (1997).
239. Chen, X., Murawski, A., Patel, K., Crespi, C. L. &Balimane, P. V. A novel design of artificial membranefor improving the parallel artificial membranepermeability assay model. Pharm. Res. 25,1511-1520 (2008).