Abstract
Combination of the in vitro models that are high throughput but less predictive and the in vivo models that are low throughput but more predictive is used effectively to evaluate the intestinal permeability and transport characteristics of a large number of drug candidates during lead selection and lead optimization processes. Parallel artificial membrane permeability assay and Caco-2 cells are the most frequently used in vitro models to assess intestinal permeability. The popularity of these models stems from their potential for high throughput, cost effectiveness, and adequate predictability of absorption potential in humans. However, several caveats associated with these models (eg, poor predictability for transporter-mediated and paracellularly absorbed compounds, significant nonspecific binding to cells/devices leading to poor recovery, variability associated with experimental factors) need to be considered carefully to realize their full potential. P-glycoprotein, among other pharmaceutically relevant transporters, has been well demonstrated to be the major determinant of drug disposition. The review article presents an objective analysis of the permeability and transporter models currently being used in the pharmaceutical industry and could help guide the discovery scientists in implementing these models in an optimal fashion.
Similar content being viewed by others
References
Food and Drug Administration.Challenges and Opportunity on the Critical Path to New Medical Products.FDA Report. Rockville, MD: Food and Drug Administration; 2004.
Kola I, Landis J. Can pharmaceutical industry reduce attrition rates?Nat Rev Drug Discov. 2004;3:711–715.
Balimane PV, Chong S, Morrison RA. Current methodologies used for evaluation of intestinal permeability and absorption.J Pharmacol Toxicol Methods. 2000;44:301–312.
Hidalgo I. Assessing the absorption of new pharmaceuticals.Curr Top Med Chem. 2001;1:385–401.
Hillgren K, Kato A, Borchardt R. In vitro systems for studying intestinal drug absorption.Med Res Rev. 1995;15:83–109.
Lipinski C, Lombardo F, Dominy B, Feeney P. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.Adv Drug Deliv Rev. 2001;46:3–26.
Avdeef A. Physicochemical profiling (solubility, permeability and charge state).Curr Top Med Chem. 2001;1:277–351.
Lin J. Drug-drug interaction mediated by inhibition and induction of P-glycoprotein.Adv Drug Deliv Rev. 2003;55:53–81.
Polli J, Jerrett J, Studenberg J, et al. Role of P-gp on CNS disposition of amprenavir, an HIV protease inhibitor.Pharm Res. 1999;16:1206–1212.
Kim R, Wendel C, Leake B, et al. Interrelationship between substrates and inhibitors of human CYP3A and P-gp.Pharm Res. 1999;16:408–414.
Lin J, Yamazaki M. Role of P-glycoprotein in pharmacokinetics.Clin Pharmacokinet. 2003;42:59–98.
Simpson K, Jarvis B. Fexofenadine: a review of its use in the management of seasonal allergic rhinitis and chronic idiopathic urticaria.Drugs. 2000;59:301–321.
Watanabe T, Miyauchi S, Sawada Y, et al Kinetic analysis of hepatobiliary transport of vincristine in perfused rat liver: possible roles of P-gp in biliary excretion of vincristine.J Hepatol. 1992;16:77–88.
Adachi Y, Suzuki H, Sugiyama Y. Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-gp.Pharm Res. 2001;18:1660–1668.
Perloff M, Stromer E, von Moltke L, Greenblatt D. Rapid assessment of P-gp inhibition and induction in vitro.Pharm Res. 2003;20:1177–1183.
Polli J, Wring S, Humphreys J, et al. Rational use of in vitro P-gp assays in drug discovery.J Pharmacol Exp Ther. 2001;299:620–628.
Yamazaki M, Neway W, Ohe T, et al. In vitro substrate identification studies for P-gp mediated transport: species difference and predictability of in vivo results.J Pharmacol Exp Ther. 2001;296:723–735.
Kansy M, Senner F, Gubernator K. Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes.J Med Chem. 1998;41:1007–1010.
Kerns E. High throughput physicochemical profiling for drug discovery.J Pharm Sci. 2001;90:1838–1858.
Ruell JA, Tsinman KL, Avdeef A. PAMPA—a drug absorption in vitro model. 5. Unstirred water layer in iso-pH mapping assays and pKa(flux)—optimized design (pOD-PAMPA).Eur J Pharm Sci. 2003;20:393–402.
Di L, Kerns EH, Fan K, McConnell OJ, Carter GT. High throughput artificial membrane permeability assay for blood-brain barrier.Eur J Med Chem. 2003;38:223–232.
Artursson P. Cell cultures as models for drug absorption across the intestinal mucosa.Crit Rev Ther Drug Carrier Syst. 1991;8:305–330.
Artursson P, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelia (Caco-2) cells.Biochem Biophys Res Commun. 1991;175:880–890.
Rubas W, Cromwell M, Shahrokh Z, et al. Flux measurements across Caco-2 monolayers may predict transport in human large intestinal tissue.J Pharm Sci. 1996;85:165–169.
Aungst B, Nguyen N, Bulgarelli J, Oates-Lenz K. The influence of donor and reservoir additives on Caco-2 perm eability and secretory transport of HIV protease inhibitors and other lipophilic compounds.Pharm Res. 2000;17:1175–1180.
Balimane PV, Chong S. A combined cell based approach to identify P-glycoprotein substrates and inhibitors in a single assay.Int J Pharm. 2005;301:80–88.
Braun A, Hammerle S, Suda K, Rothen-Rutishauser B, Gunthert M, Wunderli-Allenspach H. Cell cultures as tools in biopharmacy.Eur J Pharm Sci. 2000;11:S51-S60.
Horie K, Tang F, Borchardt R. Isolation and characterization of Caco-2 subclones expressing high levels of multidrug resistance efflux transporter.Pharm Res. 2003;20:161–168.
Ungell AL. Caco-2 replace or refine?Drug Discov Today Technol. 2004;1:423–430.
Balimane PV, Chong S. Cell culture-based models for intestinal permeability: a critique.Drug Discov Today. 2005;10:335–343.
Chong S, Dando S, Soucek K, Morrison R. In vitro permeability through Caco-2 cells is not quantitatively predictive of in vivo absorption for peptide-like drugs absorbed via the dipeptide transporter system.Pharm Res. 1996;13:120–123.
Ano R, Kimura Y, Shima M, Matsuno R, Ueno T, Akamatsu M. Relationship between structure and high-throughput screening permeability of papetide derivatives and related compounds with artificial membranes: application to prediction of Caco-2 cell permeability.Bioorg Med Chem. 2004;12:257–264.
Kerns E, 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.
Dressman J, Berardi R, Dermentzoglou L, et al. Upper gastrointestinal (GI) pH in young, healthy men and women.Pharm Res. 1990;7:756–761.
Russell T, Berardi R, Barnett J, et al. Upper gastrointestinal pH in 79 healthy, elderly, North American men and women.Pharm Res. 1993;10:187–196.
Anderle P, Huang Y, Sadee W. Intestinal membrane transport of drugs and nutrients: genomic membrane transporters using expression microarray.Eur J Pharm Sci. 2004;21:17–24.
Behrens I, Kamm W, Dantzig A, Kissel T. Variation of peptide transporter (PepT1 and HPT1) expression in Caco-2 cells as a function of cell origin.J Pharm Sci. 2004;93:1743–1754.
Sun D, Lennernas H, Welage L, et al. Comparison of human duodenum and Caco-2 gene expression profiles for 12 000 gene sequence tags and correlation with permeability of 26 drugs.Pharm Res. 2002;19:1400–1416.
Krishna G, Chen K, Lin C, Nomeir A. Permeability of lipophilic compounds in drug discovery using in vitro human absorption model, Caco-2.Int J Pharm. 2001;222:77–89.
Saha P, Kou J. Effect of bovine serum albumin on drug permeability estimation across Caco-2 monolayers.Eur J Pharm Biopharm. 2002;54:319–324.
Dimitrijevic D, Shaw A, Florence A. Effects of some non-ionic surfactants on transepithelial permeability in Caco-2 cells.J Pharm Pharmacol. 2000;52:157–162.
Rege B, Yu L, Hussain A, Polli J. Effect of common excipients on Caco-2 transport of low-permeability drugs.J Pharm Sci. 2001;90:1776–1786.
Rege B, Kao J, Polli J. Effect of non-ionic surfactants on membrane transport in Caco-2 cell monolayers.Eur J Pharm Sci. 2002;16:237–246.
Ingels F, Augustijns P. Biological, pharmaceutical, and analytical considerations with respect to the transport media used in the absorption screening system, Caco-2.J Pharm Sci. 2003;92:1545–1558.
Walter E, Kissel T. Heterogeneity in the human intestinal cell line Caco-2 leads to differences in transepithelial transport.Eur J Pharm Sci. 1995;3:215–230.
Maliepaard M, van Gastelen M, Tohgo A, et al. Circum vention of BCRP-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF120918.Clin Cancer Res. 2001;7:935–941.
Woehlecke H, Pohl A, Alder-Berens N, Lage H, Herrmann A. Enhanced exposure of phosphatidylserine in human gastric carcinoma cells overexpressing the half-size ABC transporter BCRP (ABCG2).Biochem J. 2003;376:489–495.
Chen Z, Kawabe T, Ono M, et al. Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter.Mol Pharmacol. 1999;56:1219–1228.
Dantzig A, Shepard R, Law K, et al. Selectivity of the multidrug resistance modulator, LY335979, for P-glycoprotein and effect on cytochrome P-450 activities.J Pharmacol Exp Ther. 1999;290:854–862.
Volk E, Schneider E. Wild type BCRP is a methotrexate polyglutamate transporter.Cancer Res. 2003;63:5538–5543.
Zhang S, Yang X, Morris M. Flavonoids are inhibitors of BCRP-mediated transport.Mol Pharmacol. 2004;65:1208–1216.
Lee K, Ng C, Brouwer KL, Thakker DR. Secretory transport of ranitidine and famotidine across Caco-2 cell monolayers.J Pharmacol Exp Ther. 2002;303:574–580.
Author information
Authors and Affiliations
Corresponding author
Additional information
Published: January 13, 2006
Rights and permissions
About this article
Cite this article
Balimane, P.V., Han, YH. & Chong, S. Current industrial practices of assessing permeability and P-glycoprotein interaction. AAPS J 8, 1 (2006). https://doi.org/10.1208/aapsj080101
Received:
Accepted:
Published:
DOI: https://doi.org/10.1208/aapsj080101