Skip to main content
SpringerLink
Log in

Predicting P-Glycoprotein Effects on Oral Absorption: Correlation of Transport in Caco-2 with Drug Pharmacokinetics in Wild-Type and mdr1a(-/-) Mice in Vivo

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. Cell-based permeability screens are widely used to identify drug-P-glycoprotein (PGP) interaction in vitro. However, their reliability in predicting the impact of PGP on human drug pharmacokinetics is poorly defined. The aim was to determine whether a quantitative relationship exists between PGP-mediated alterations in Caco-2 permeability and oral pharmacokinetics in mice.

Methods. Two indicators of drug efflux were measured in Caco-2 for a group of 10 compounds, the ratio of A-B and B-A transport (RB-A/A-B) and the ratio of A-B transport in the presence and absence of a PGP inhibitor, GF120918 (RGF). These data were correlated with ratios of oral plasma levels in either mdr1a(-/-) or mdr1a/1b(-/-) and wild-type mice (RKO/WT in vivo) calculated from literature data on these compounds.

Results. A significant, positive correlation (r2= 0.8, p \h 0.01) was observed between RGF and RKO/WT in vivo. In contrast, RB-A/A-B, a more commonly used in vitro measure, showed a much weaker correlation with in vivo data (r2= 0.33, p = 0.11). A strong correlation with RGF was also observed after correction of in vivo data for PGP effects on IV clearance.

Conclusion. The increase in A-B drug permeability following inhibition of PGP in Caco-2 allows a reasonable prediction of the likely in vivo impact that PGP will have on plasma drug levels after oral administration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

references

  1. A. H. Schinkel and J. W. Jonker. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv. Drug Deliv. Rev. 55:3–29 (2003).

    Google Scholar 

  2. A. Ayrton and P. Morgan. Role of transport proteins in drug absorption, distribution and excretion. Xenobiotica 31:469–497 (2001).

    Google Scholar 

  3. H. Kusuhara and Y. Sugiyama. Role of transporters in the tissue-selective distribution and elimination of drugs: transporters in the liver, small intestine, brain and kidney. J. Controlled Release 78:43–54 (2002).

    Google Scholar 

  4. J. H. Lin and M. Yamazaki. Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin. Pharmacokinet. 42:59–98 (2003).

    Google Scholar 

  5. J. H. Lin. Drug-drug interaction mediated by inhibition and induction of P-glycoprotein. Adv. Drug Deliv. Rev. 55:53–81 (2003).

    Google Scholar 

  6. R. H. Stephens, C. A. O'Neill, A. Warhurst, G. L. Carlson, M. Rowland, and G. Warhurst. Kinetic profiling of P-glycoprotein-mediated drug efflux in rat and human intestinal epithelia. J. Pharmacol. Exp. Ther. 296:584–591 (2001).

    Google Scholar 

  7. A. Garrigues, J. Nugier, J. Orlowski, and E. Ezan. A high-throughput screening microplate test for the interaction of drugs with P-glycoprotein. Anal. Biochem. 305:106–114 (2002).

    Google Scholar 

  8. Y. Zhang, C. Bachmeier, and D. W. Miller. In vitro and in vivo models for assessing drug efflux transporter activity. Adv. Drug Deliv. Rev. 55:31–51 (2003).

    Google Scholar 

  9. J. H. Hochman, M. Yamazaki, T. Ohe, and J. H. Lin. Evaluation of drug interactions with P-glycoprotein in drug discovery: in vitro assessment of the potential for drug-drug interactions with P-glycoprotein. Curr. Drug Metab. 3:257–273 (2002).

    Google Scholar 

  10. J. W. Polli, S. A. Wring, J. E. Humphreys, L. Y. Huang, J. B. Morgan, L. O. Webster, and C. S. Serabjit-Singh. Rational use of in vitro P-glycoprotein assays in drug discovery. J. Pharmacol. Exp. Ther. 299:620–628 (2001).

    Google Scholar 

  11. A. H. Schinkel, U. Mayer, E. Wagenaar, C. A. A. M. Mol, L. van Deemter, J. J. M. Smit, M. A. van der Valk, A. C. Voordouw, H. Spits, O. van Tellingen, J. M. J. M. Zijlmans, W. E. Fibbe, and P. Borst. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc. Natl. Acad. Sci. USA 94:4028–4033 (1997).

    Google Scholar 

  12. C. P. Chen, X. R. Liu, and B. J. Smith. Utility of mdr1-gene deficient mice in assessing the impact of P-glycoprotein on pharmacokinetics and pharmacodynamics in drug discovery and development. Curr. Drug. Metab. 4:272–291 (2003).

    Google Scholar 

  13. R. H. Stephens, C. A. O'Neill, J. Bennett, M. Humphrey, B. Henry, M. Rowland, and G. Warhurst. Resolution of P-glycoprotein and non-P-glycoprotein effects on drug permeability using intestinal tissues from mdr1a(-/-) mice. Br. J. Pharmacol. 135:2038–2046 (2002).

    Google Scholar 

  14. Y. Adachi, H. Suzuki, and Y. Sugiyama. Comparative studies of in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm. Res. 18:1660–1668 (2001).

    Google Scholar 

  15. R. H. Stephens, C. A. O'Neill, A. Warhurst, G. L. Carlson, M. Rowland, and G. Warhurst. Kinetic profiling of P-glycoprotein-mediated drug efflux in rat and human intestinal epithelia. J. Pharmacol. Exp. Ther. 296:584–591 (2001).

    Google Scholar 

  16. U. I. Schwarz, G. K. Dresser, and R. B. Kim. MDR1 gene-dose effect in mice. Clin. Pharm. Ther. 69:P85(2001).

    Google Scholar 

  17. C. Dagenais, J. Zong, J. Ducharme, and G. M. Pollack. Effect of mdr1a P-glycoprotein gene disruption, gender, and substrate concentration on brain uptake of selected compounds. Pharm. Res. 18:957–963 (2001).

    Google Scholar 

  18. A. Sparreboom, J. vanAsperen, U. Mayer, A. H. Schinkel, J. W. Smit, D. K. F. Meijer, P. Borst, W. J. Nooijen, J. H. Beijnen, and O. vanTellingen. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc. Natl. Acad. Sci. USA 94:2031–2035 (1997).

    Google Scholar 

  19. U. Mayer, E. Wagenaar, J. H. Beijnen, J. W. Smit, D. K. F. Meijer, J. vanAsperen, P. Borst, and A. H. Schinkel. Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr1a P-glycoprotein. Brit. J. Pharm. 119:1038–1044 (1996).

    Google Scholar 

  20. R. B. Kim, W. F. Fromm, C. Wandel, B. Leake, A. J. J. Wood, D. M. Roden, and G. R. Wilkinson. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J. Clin. Invest. 101:289–294 (1998).

    Google Scholar 

  21. J. W. Jonker, J. W. Smit, R. F. Brinkhuis, M. Maliepaard, J. H. Beijnen, J. H. M. Schellens, and A. H. Schinkel. Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J. Nat. Cancer Inst. 92:1651–1656 (2000).

    Google Scholar 

  22. U. I. Schwarz, G. K. Dresser, and R. B. Kim. Talinolol-verapamil interaction is not solely due to P-glycoprotein inhibition. Clin. Pharm. Ther. 69:P85-P85 (2001).

    Google Scholar 

  23. E. G. Schuetz, A. H. Schinkel, M. V. Relling, and J. D. Schuetz. P-glycoprotein: A major determinant of rifampicin-inducible expression of cytochrome P4503A in mice and humans. Proc. Natl. Acad. Sci. USA 93:4001–4005 (1996).

    Google Scholar 

  24. K. Beaumont, A. Harper, D. A. Smith and J. Bennett. The role of P-glycoprotein in determining the oral absorption and clearance of the NK2 antagonist, UK-224,671. Eur. J. Pharm. Sci. 12:41–50 (2000).

    Google Scholar 

  25. K. Yokogawa, M. Takahashi, I. Tamai, H. Konishi, M. Nomura, S. Moritani, K. Miyamoto, and A. Tsuji. P-glycoprotein-dependent disposition kinetics of tacrolimus: studies in mdr1a knockout mice. Pharm. Res. 16:1213–1218 (1999).

    Google Scholar 

  26. P. S. Burton, J. T. Goodwin, T. J. Vidmar, and B. M. Amore. Predicting drug absorption: how nature made it a difficult problem. J. Pharmacol. Exp. Ther. 303:889–895 (2002).

    Google Scholar 

  27. L. Z. Benet and C. L. Cummins. The drug efflux – metabolism alliance: biochemical aspects. Adv. Drug Del. Rev. 50:S3-S11 (2001).

    Google Scholar 

  28. R. H. Stephens, J. Tanianis-Hughes, N. B. Higgs, M. Humphrey, and G. Warhurst. Region dependent modulation of intestinal permeability by drug efflux transporters: in vitro studies in mdr1a (-/-) mouse intestine. J. Pharmacol. Exp. Ther. 303:1095–1101 (2002).

    Google Scholar 

  29. M. Lindell, M. Lang, and H. Lennernas. Expression of genes encoding for drug metabolising cytochrome P450 enzymes and P-glycoprotein in the rat small intestine; comparison to the liver. Eur. J. Drug Metab. Pharmacokinet 28:41–48 (2003).

    Google Scholar 

  30. E. G. Schuetz, D. R. Umbenhauer, K. Yasuda, C. Brimer, L. Nguyen, M. V. Relling, J. D. Schuetz, and A. H. Schinkel. Altered expression of hepatic cytochromes P-450 in mice deficient in one or more mdr1 genes. Molec. Pharm. 57:188–197 (2000).

    Google Scholar 

  31. M. D. Troutman and D. R. Thakker. Novel experimental parameters to quantify the modulation of absorptive and secretory transport of compounds by P-glycoprotein in cell culture models of intestinal epithelium. Pharm. Res. 20:1210–1224 (2003).

    Google Scholar 

  32. Y. Adachi, H. Suzuki, and Y. Sugiyama. Quantitative evaluation of the function of small intestinal P-glycoprotein: comparative studies between in situ and in vitro. Pharm. Res. 20:1163–1169 (2003).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Gut Barrier Group, Schools of Medicine and Pharmacy (, University of Manchester), Hope Hospital, Salford, M6 8HD, UK

    Andrew Collett, Jolanta Tanianis-Hughes, David Hallifax & Geoff Warhurst

  2. Centre for Applied Pharmacokinetic Research, Schools of Medicine and Pharmacy (, University of Manchester), Hope Hospital, Salford, M6 8HD, UK

    Andrew Collett, Jolanta Tanianis-Hughes & Geoff Warhurst

Authors
  1. Andrew Collett
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jolanta Tanianis-Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Hallifax
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Geoff Warhurst
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Geoff Warhurst.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Collett, A., Tanianis-Hughes, J., Hallifax, D. et al. Predicting P-Glycoprotein Effects on Oral Absorption: Correlation of Transport in Caco-2 with Drug Pharmacokinetics in Wild-Type and mdr1a(-/-) Mice in Vivo . Pharm Res 21, 819–826 (2004). https://doi.org/10.1023/B:PHAM.0000026434.82855.69

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:PHAM.0000026434.82855.69

Search

Navigation