The AAPS Journal

, Volume 8, Issue 1, pp E1–E13 | Cite as

Current industrial practices of assessing permeability and P-glycoprotein interaction

Article

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.

Keywords

permeability high throughput Caco-2 cells transporters drug discovery PAMPA P-gp 

References

  1. 1.
    Food and Drug Administration.Challenges and Opportunity on the Critical Path to New Medical Products.FDA Report. Rockville, MD: Food and Drug Administration; 2004.Google Scholar
  2. 2.
    Kola I, Landis J. Can pharmaceutical industry reduce attrition rates?Nat Rev Drug Discov. 2004;3:711–715.CrossRefPubMedGoogle Scholar
  3. 3.
    Balimane PV, Chong S, Morrison RA. Current methodologies used for evaluation of intestinal permeability and absorption.J Pharmacol Toxicol Methods. 2000;44:301–312.CrossRefPubMedGoogle Scholar
  4. 4.
    Hidalgo I. Assessing the absorption of new pharmaceuticals.Curr Top Med Chem. 2001;1:385–401.CrossRefPubMedGoogle Scholar
  5. 5.
    Hillgren K, Kato A, Borchardt R. In vitro systems for studying intestinal drug absorption.Med Res Rev. 1995;15:83–109.CrossRefPubMedGoogle Scholar
  6. 6.
    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.CrossRefPubMedGoogle Scholar
  7. 7.
    Avdeef A. Physicochemical profiling (solubility, permeability and charge state).Curr Top Med Chem. 2001;1:277–351.CrossRefPubMedGoogle Scholar
  8. 8.
    Lin J. Drug-drug interaction mediated by inhibition and induction of P-glycoprotein.Adv Drug Deliv Rev. 2003;55:53–81.CrossRefPubMedGoogle Scholar
  9. 9.
    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.CrossRefPubMedGoogle Scholar
  10. 10.
    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.CrossRefPubMedGoogle Scholar
  11. 11.
    Lin J, Yamazaki M. Role of P-glycoprotein in pharmacokinetics.Clin Pharmacokinet. 2003;42:59–98.CrossRefPubMedGoogle Scholar
  12. 12.
    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.CrossRefPubMedGoogle Scholar
  13. 13.
    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.CrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    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.CrossRefPubMedGoogle Scholar
  16. 16.
    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.PubMedGoogle Scholar
  17. 17.
    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.PubMedGoogle Scholar
  18. 18.
    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.CrossRefPubMedGoogle Scholar
  19. 19.
    Kerns E. High throughput physicochemical profiling for drug discovery.J Pharm Sci. 2001;90:1838–1858.CrossRefPubMedGoogle Scholar
  20. 20.
    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.CrossRefPubMedGoogle Scholar
  21. 21.
    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.CrossRefPubMedGoogle Scholar
  22. 22.
    Artursson P. Cell cultures as models for drug absorption across the intestinal mucosa.Crit Rev Ther Drug Carrier Syst. 1991;8:305–330.PubMedGoogle Scholar
  23. 23.
    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.CrossRefPubMedGoogle Scholar
  24. 24.
    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.CrossRefPubMedGoogle Scholar
  25. 25.
    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.CrossRefPubMedGoogle Scholar
  26. 26.
    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.CrossRefPubMedGoogle Scholar
  27. 27.
    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.CrossRefPubMedGoogle Scholar
  28. 28.
    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.CrossRefPubMedGoogle Scholar
  29. 29.
    Ungell AL. Caco-2 replace or refine?Drug Discov Today Technol. 2004;1:423–430.CrossRefPubMedGoogle Scholar
  30. 30.
    Balimane PV, Chong S. Cell culture-based models for intestinal permeability: a critique.Drug Discov Today. 2005;10:335–343.CrossRefPubMedGoogle Scholar
  31. 31.
    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.CrossRefPubMedGoogle Scholar
  32. 32.
    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.CrossRefPubMedGoogle Scholar
  33. 33.
    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.CrossRefPubMedGoogle Scholar
  34. 34.
    Dressman J, Berardi R, Dermentzoglou L, et al. Upper gastrointestinal (GI) pH in young, healthy men and women.Pharm Res. 1990;7:756–761.CrossRefPubMedGoogle Scholar
  35. 35.
    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.CrossRefPubMedGoogle Scholar
  36. 36.
    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.CrossRefPubMedGoogle Scholar
  37. 37.
    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.CrossRefPubMedGoogle Scholar
  38. 38.
    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.CrossRefPubMedGoogle Scholar
  39. 39.
    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.CrossRefPubMedGoogle Scholar
  40. 40.
    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.CrossRefPubMedGoogle Scholar
  41. 41.
    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.CrossRefPubMedGoogle Scholar
  42. 42.
    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.CrossRefPubMedGoogle Scholar
  43. 43.
    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.CrossRefPubMedGoogle Scholar
  44. 44.
    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.CrossRefPubMedGoogle Scholar
  45. 45.
    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.CrossRefGoogle Scholar
  46. 46.
    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.PubMedGoogle Scholar
  47. 47.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    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.PubMedGoogle Scholar
  49. 49.
    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.PubMedGoogle Scholar
  50. 50.
    Volk E, Schneider E. Wild type BCRP is a methotrexate polyglutamate transporter.Cancer Res. 2003;63:5538–5543.PubMedGoogle Scholar
  51. 51.
    Zhang S, Yang X, Morris M. Flavonoids are inhibitors of BCRP-mediated transport.Mol Pharmacol. 2004;65:1208–1216.CrossRefPubMedGoogle Scholar
  52. 52.
    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.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2006

Authors and Affiliations

  • Praveen V. Balimane
    • 1
  • Yong-Hae Han
    • 1
  • Saeho Chong
    • 1
  1. 1.Department of Metabolism and Pharmacokinetics, Pharmaceutical Candidate OptimizationBristol-Myers Squibb Pharmaceutical Research InstitutePrinceton

Personalised recommendations