Strategies to Overcome Efflux Pumps

Chapter

Abstract

Intestinal efflux pumps such as P-glycoprotein play a significant role in altering the absorption of a wide range of drugs. Anticancer agents, antibiotics, antivirals, calcium channel blockers, immunosuppressive agents, peptide drugs and several other therapeutic compounds have been reported to be substrates of one or more transmembrane efflux transporters.

Inhibition of these efflux pumps by various compounds can lead to enhanced absorption of several drugs across the intestine.

In this chapter, several efflux pump inhibitors such as low molecular mass inhibitors, polymeric inhibitors and advanced formulation approaches on how to overcome drug efflux are discussed.

Keywords

Surfactant Chitosan Doxorubicin Cyclosporine Alginate 

References

  1. Al-Shawi M.K., Urbatsch I.L., Senior A.E. (1994) Covalent inhibitors of P-glycoprotein ATPase activity, J Biol Chem 269(12):8986–8992.PubMedGoogle Scholar
  2. Balayssac D., Authier N., Cayre A., Coudore F. (2005) Does inhibition of P-glycoprotein lead to drug-drug interactions? Toxicol Lett, 156(3):319–329.PubMedCrossRefGoogle Scholar
  3. Bardelmeijer H.A., Beijnen J.H., Brouwer K.R., Rosing H., Nooijen W.J., Schellens J.H., van Tellingen O. (2000). Increased oral bioavailability of paclitaxel by GF120918 in mice through selective modulation of P-glycoprotein. Clin Cancer Res, 6:4416–4421.PubMedGoogle Scholar
  4. Batrakova E.V., Han H.Y., Alakhov V.Y., Miller D.W., Kabanov A.V. (1998) Effects of pluronic block copolymers on drug absorption in Caco-2 cell monolayers. Pharm Res, 15(6):850–855.PubMedCrossRefGoogle Scholar
  5. Bogman K., Zysset Y., Degen L., Hopfgartner G., Gutmann H., Alsenz J., Drewe J. (2005) P-glycoprotein and surfactants: effect on intestinal talinolol absorption. Clin Pharmacol Ther, 77(1):24–32.PubMedCrossRefGoogle Scholar
  6. Carreno-Gomez B. and Duncan R. Compositions with enhanced oral bioavailability. US patent, 2002.Google Scholar
  7. Choi J.S. and Jo B.W. (2004) Enhanced paclitaxel bioavailability after oral administration of pegylated paclitaxel prodrug for oral delivery in rats. Int J Pharm, 280:221–722.PubMedCrossRefGoogle Scholar
  8. Collnot E.M., Baldes C., Wempe M.F., Hyatt J., Navarro L., Edgar K.J., Schaefer U.F., Lehr C.M. (2006) Influence of vitamin E TPGS poly(ethlyene glycol) chain length on apical efflux transporters in Caco-2 cell monolayers. J Control Release, 111:35–40.PubMedCrossRefGoogle Scholar
  9. Fisher M., Abramov M., Van Aerschot A., Xu D., Juliano R.L., Herdewijn P. (2007) Inhibition of MDR1 expression with altritol-modified siRNAs. Nucleic Acids Res, 35(4):1064–1074.PubMedCrossRefGoogle Scholar
  10. Floren L.C., Bekersky I., Benet L.Z., Mekki Q., Dressler D., Lee J.W., Roberts J.P., Hebert M.F. (2001) Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin Pharmacol Ther, 62:41–49.CrossRefGoogle Scholar
  11. Föger F., Hoyer H., Kafedjiiski K., Thaurer M., Bernkop-Schnürch A. (2006a) In vivo comparison of various polymeric and low molecular mass inhibitors of intestinal P-glycoprotein. Biomaterials, 27, (34), 5855–5860.PubMedCrossRefGoogle Scholar
  12. Föger F., Kafedjiiski K., Hoyer H., Loretz B., Bernkop-Schnürch A. (2006b) Enhanced transport of P-glycoprotein substrate saquinavir in presence of thiolated chitosan. J Drug Targ, 15, (2), 132–139.CrossRefGoogle Scholar
  13. Föger, F., Schmitz T. and Bernkop-Schnürch A. (2006c) In vivo evaluation of an oral delivery system for P-gp substrates based on thiolated chitosan. Biomaterials, 27, (23), 4250–4255.PubMedCrossRefGoogle Scholar
  14. Föger F., Malaivijitnond S., Wannaprasert T., Huck C., Bernkop-Schnürch A., Werle M. (2008) Effect of oral paclitaxel in presence of a thiolated polymer on absorption and tumor growth in rats. J Drug Targeting, 16, (2), 149–55.Google Scholar
  15. Germann U.A., Shlyakhter D., Mason V.S., Zelle R.E., Duffy J.P., Galullo V., Armistead D.M., Saunders J.O., Boger J., Harding M.W. (1997) Cellular and biochemical characterization of VX-710 as a chemosensitizer: Reversal of P-glycoprotein-mediated multidrug resistance in vitro. Anticancer Drugs, 8:125–140.PubMedCrossRefGoogle Scholar
  16. Gerrard G., Payne E., Baker R.J., Jones D.T., Potter M., Prentice H.G. (2004) Clinical effects and P-glycoprotein inhibition in patients with acute myeloid leukaemia treated with zosuquidar trihydrochloride, daunorubicin and cytarabine, Haematologica 89:782–790.PubMedGoogle Scholar
  17. Grabovac V., Bernkop-Schnürch A. (2006) Thiolated polymers as effective inhibitors of intestinal Mrp2 efflux pump transporters. Sci Pharm, 74.Google Scholar
  18. Hugger E.D., Audus K.L., and Borchardt R.T. (2002) Effects of poly(ethylene glycol) on efflux transporter activity in Caco-2 cell monolayers. J Pharm Sci, 91:1980–1990.PubMedCrossRefGoogle Scholar
  19. Hunter J., Hirst B.H. (1997) Intestinal secretion of drugs. The role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption, Adv Drug Deliv Rev 25:129–157.CrossRefGoogle Scholar
  20. Jain R., Majumdar S., Nashed Y., Pal D., Mitra A.K. (2004) Circumventing P-glycoprotein-mediated cellular efflux of quinidine by prodrug derivatization. Mol Pharm, 1(4):290–299.PubMedCrossRefGoogle Scholar
  21. Jain R., Duvvuri S., Kansara V., Mandava N.K., Mitra A.K. (2007) Intestinal absorption of novel-dipeptide prodrugs of saquinavir in rats. Int J Pharm, 336: 233–240.PubMedCrossRefGoogle Scholar
  22. Johnson B.M., Charman W.N., Porter C.J.H. (2002) An in vitro examination of the impact of polyehtylene glycol 400, pluronic P85 and vitamin E D-a-tocopheryl polyethylene glycol 1000 succinate on p-glycoprotein efflux and enterocyte-based metabolism in excised rat intestine. AAPS PharmSci, 4: 1–13.CrossRefGoogle Scholar
  23. Kim R.B. (2002) Drugs as P-glycoprotein substrates, inhibitors, and inducers, Drug Metab Rev, 34:47–54.PubMedCrossRefGoogle Scholar
  24. Kimura Y., Aoki J., Kohno M., Ooka H., Tsuruo T., Nakanishi O. (2002) P-glycoprotein inhibition by the multidrug resistance-reversing agent MS-209 enhances bioavailability and antitumor efficacy of orally administered paclitaxel. Cancer Chemother Pharmacol, 49:322–328.PubMedCrossRefGoogle Scholar
  25. Kuppens I.E., Bosch T.M., van Maanen M.J., Rosing H., Fitzpatrick A., Beijnen J.H., Schellens J.H. (2005) Oral bioavailability of docetaxel in combination with OC144-093 (ONT-093). Cancer Chemother Pharmacol, 55:72–78.PubMedCrossRefGoogle Scholar
  26. Lacombe O., Woodley J., Solleux C., Delbos J.M., Boursier-Neyret C., Houin G. (2004) Localisation of drug permeability along the rat small intestine, using markers of the paracellular, transcellular and some transporter routes. Eur J Pharm Sci, 23:385–391.PubMedCrossRefGoogle Scholar
  27. Lennernas H. (2003) Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet, 42:1141–1160.PubMedCrossRefGoogle Scholar
  28. Leu B.L., Huang J.D. (1995) Inhibition of intestinal Pglycoprotein and effects on etoposide absorption. Cancer Chemother Pharmacol, 35:432–436.PubMedCrossRefGoogle Scholar
  29. Lin Y., Shen Q., Katsumi H., Okada N., Fujita T., Jiang X., Yamamoto A. (2007) Effects of Labrasol and Other Pharmaceutical Excipients on the Intestinal Transport and Absorption of Rhodamine123, a P-Glycoprotein Substrate, in Rats. Biol Pharm Bull, 30(7) 1301–1307.PubMedCrossRefGoogle Scholar
  30. Liu C., Wu J., Shi B., Zhang Y., Gao T., Pei Y. (2006) Enhancing the bioavailability of cyclosporine a using solid dispersion containing polyoxyethylene (40) stearate. Drug Dev Ind Pharm, 32:115–123.PubMedCrossRefGoogle Scholar
  31. Lo Y.L. (2003) Relationships between the hydrophilic–lipophilic balance values of pharmaceutical excipients and their multidrug resistance modulating effect in Caco-2 cells and rat intestines. J Control Release, 90:37–48.PubMedCrossRefGoogle Scholar
  32. Malingre M.M., Ten Bokkel Huinink W.W., Mackay M., Schellens J.H., Beijnen J.H. (2001) Pharmacokinetics of oral cyclosporin A when co-administered to enhance the absorption of orally administered docetaxel. Eur J Clin Pharmacol, 57:305–307.PubMedCrossRefGoogle Scholar
  33. Palmberger T.F., Hombach J., Bernkop-Schnürch A. (2008) Thiolated chitosan: Development and in vitro evaluation of an oral delivery system for acyclovir. Int J Pharm, 348(1–2):79–85.Google Scholar
  34. Shen Q., Lin Y., Handa T., Doi M., Sugie M., Wakayama K., Okada N., Fujita T., Yamamoto A. (2006) Modulation of intestinal P-glycoprotein function by polyethylene glycols and their derivatives by in vitro transport and in situ absorption studies. Int J Pharm, 313:49–56.PubMedCrossRefGoogle Scholar
  35. Shono Y., Nishihara H., Matsuda Y., Furukawa S., Okada N., Fujita T., Yamamoto A. (2004) Modulation of intestinal P- glycoprotein function by cremophor EL and other surfactants by an in vitro diffusion chamber method using the isolated rat intestinal membranes. J Pharm Sci, 93:877–885.PubMedCrossRefGoogle Scholar
  36. Twentyman P.R., Bleehen N.M. (1991) Resistance modification by PSC-833, a novel non-immunosuppressive cyclosporin. Eur J Cancer, 27:1639–1642.PubMedCrossRefGoogle Scholar
  37. van Asperen J., van Tellingen O., Sparreboom A., Schinkel A.H., Borst P., Nooijen W.J., Beijnen J.H. (1997) Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833. Br J Cancer, 76:1181–1183.PubMedCrossRefGoogle Scholar
  38. Varma M.V., Ashokraj Y., Dey C.S., Panchagnula R. (2003) P-glycoprotein inhibitors and their screening: A perspective from bioavailability enhancement. Pharmacol Res, 48:347–359.PubMedCrossRefGoogle Scholar
  39. Varma M.V., Panchagnula R. (2005) Enhanced oral paclitaxel absorption with vitamin E-TPGS: effect on solubility and permeability in vitro, in situ and in vivo. Eur J Pharm Sci, 25:445–453.PubMedCrossRefGoogle Scholar
  40. Varma M.V., Perumal O.P., Panchagnula R. (2006) Functional role of P-glycoprotein in limiting peroral drug absorption: optimizing drug delivery. Curr Opin Chem Biol, 10:367–373.PubMedCrossRefGoogle Scholar
  41. Werle M., Hoffer M. (2006) Glutathione and thiolated chitosan inhibit multidrug resistance P-glycoprotein activity in excised small intestine. J Control Rel, 111, (1–2), 41–46.CrossRefGoogle Scholar
  42. Werle M. (2008a) Polymeric and low molecular mass efflux pump inhibitors for oral drug delivery. J Pharm Sci, 97, (1), 60–70.Google Scholar
  43. Werle M. (2008b) Natural and synthetic polymers as inhibitors of drug efflux pumps. Pharm Res, 25, (3), 500–11.Google Scholar
  44. Woo J.S., Lee C.H., Shim C.K., Hwang S.J. (2003) Enhanced oral bioavailability of paclitaxel by coadministration of the P-glycoprotein inhibitor KR30031. Pharm Res, 20:24–30.PubMedCrossRefGoogle Scholar
  45. Yumoto R., Murakami T., Nakamoto Y., Hasegawa R., Nagai J., Takano M. (1999) Transport of rhodamine 123, a P-glycoprotein substrate, across rat intestine and Caco-2 cell monolayers in the presence of cytochrome P-450 3A-related compounds. J Pharmacol Exp Ther, 289:149–155.PubMedGoogle Scholar
  46. Zhang H., Yao M., Morrison R.A., Chong S. (2003) Commonly used surfactant, Tween 80, improves absorption of P-glycoprotein substrate, digoxin, in rats. Arch Pharm Res, 26:768–772.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Diabetes Research Unit, Oral Formulation ResearchMålφvDenmark

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