Skip to main content

Influene of Pharmaceutical Excipients on the Membrane Transport of a P-glycoprotein Substrate in the Rat Small Intestine

European Journal of Drug Metabolism and Pharmacokinetics volume 45, pages 645–652 (2020)Cite this article

Abstract

Background and Objectives

Generic drugs are generally used worldwide because of affordability compared to brand-name drugs. One of the main differences between brand-name and generic drugs is pharmaceutical excipients. We previously reported the effects of pharmaceutical excipients on the membrane permeation of drugs via the paracellular and transcellular routes, which are passive transport routes. P-glycoprotein (P-gp) is a typical ATP-binding cassette transporter and is mostly responsible for drug–drug interactions involving transporters. In the present study, rhodamine 123 (Rho123) was selected as the P-gp substrate, and the effects of pharmaceutical excipients on its membrane transport in the rat jejunum and ileum were examined.

Methods

Twenty major pharmaceutical excipients widely used in the pharmaceutical industry were selected. The in vitro diffusion chamber method using the rat jejunum and ileum was employed to investigate the effects of pharmaceutical excipients on the membrane permeation of Rho123.

Results

The results obtained showed that the membrane permeability of Rho123 significantly (P < 0.05) changed under certain dosage conditions of pharmaceutical excipients such as sodium carboxymethyl starch, pullulan, glyceryl monostearate and so on. Furthermore, the effects of pharmaceutical excipients were site specific in the small intestine.

Conclusion

The present results demonstrated that some pharmaceutical excipients altered the membrane permeability of Rho123 in the rat small intestine.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Brady JM, Cherrington NJ, Hartley DP, Buist SC, Li N, Klaassen CD. Tissue distribution and chemical induction of multiple drug resistance genes in rats. Drug Metab Dispos. 2002;30:838–44.

    Article  CAS  Google Scholar 

  2. Fujo AT, Ueda K, Slamon DJ, Poplack DG, Gottesman MM, Pastan I. Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci USA. 1987;84:265–9.

    Article  Google Scholar 

  3. Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood–brain barrier sites. Proc Natl Acad Sci USA. 1989;86:695–8.

    Article  CAS  Google Scholar 

  4. Lum BL, Gosland MP. Pharmacologic implications for the clinica; use of P-glycoprotein inhibitors. Hematol Oncol Clin N Am. 1995;9:319–36.

    Article  CAS  Google Scholar 

  5. Russel FG, Masereeuw R, van Aubel RA. Molecular aspects of renal anionic drug transport. Annu Rev Physiol. 2002;64:563–94.

    Article  CAS  Google Scholar 

  6. Szakács G, Váradi A, Ozvegy-Laczka C, Sarkadi B. The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov Today. 2008;13:379–93.

    Article  CAS  Google Scholar 

  7. Hyde SC, Emsley P, Hartshorn MJ, Mimmack MM, Gileadi U, Pearce SR, Gallagher MP, Gill DR, Hubbard RE, Higgins CF. Structural model of ATP-binding proteins associated with cystic fibrosis, multidrug resistance and bacterial transport. Nature. 1990;346:362–5.

    Article  CAS  Google Scholar 

  8. Dean M, Hamon Y, Chimini GT. The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res. 2001;42:1007–17.

    PubMed  CAS  Google Scholar 

  9. Tomita M, Takizawa Y, Kishimoto H, Hayashi M. Assessment of ileal P-glycoprotein dysfunction induced by ischemia/reperfusion using in vivo animal model. Drug Metab Pharmacokinet. 2008;23:356–63.

    Article  CAS  Google Scholar 

  10. Takizawa Y, Kishimoto H, Kitazato T, Tomita M, Hayashi M. Changes in the localization of ileal P-glycoprotein induced by intestinal ischemia/reperfusion. Biol Pharm Bull. 2011;34:408–14.

    Article  CAS  Google Scholar 

  11. Iijima H, Kamei M, Koshimizu T, Shiragami M. Evaluation of information for generic drugs based on importance and necessity. Yakugaku Zasshi. 2005;125(9):739–47.

    Article  CAS  Google Scholar 

  12. Onda M, Kanematsu M, Kitamura T, Sakai T, Sakagami K, Tanaka K, Hamahata Y, Hirooka T, Fujii K, Matsuda M, Miki H, Mashimo H, Hada R, Arakawa Y. Availability of drug information on bioequivalence of generic products-findings of graduate interns at a university pharmacy. Yakugaku Zasshi. 2007;127(7):1159–66.

    Article  CAS  Google Scholar 

  13. Takizawa Y, Kishimoto H, Nakagawa M, Sakamoto N, Tobe Y, Furuya T, Tomita M, Hayashi M. Effects of pharmaceutical excipients on membrane permeability in rat small intestine. Int J Pharm. 2013;453:363–70.

    Article  CAS  Google Scholar 

  14. Takizawa Y, Aizawa Y, Furuya T, Hayashi M. Influence of pharmaceutical excipients on membrane transport via transcellular route in rat small intestine. Sch Acad J Pharm. 2019;8(11):488–96.

    CAS  Google Scholar 

  15. Cornaire G, Woodley J, Hermann P, Cloarec A, Arellano C, Houin G. Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo. Int J Pharm. 2005;278:119–31.

    Article  CAS  Google Scholar 

  16. Sawangrat K, Morishita M, Kusamori K, Katsumi H, Sakane T, Yamamoto A. Effects of various pharmaceutical excipients on the intestinal transport and absorption of Sulfasalazine, a typical substrate of breast cancer resistance protein transporter. J Pharm Sci. 2018;107(11):2946–56.

    Article  CAS  Google Scholar 

  17. Sawangrat K, Yamashita S, Tanaka A, Morishita M, Kusamori K, Katsumi H, Sakane T, Yamamoto A. Modulation of intestinal transport and absorption of Topotecan, a BCRP substrate, by various pharmaceutical excipients and their inhibitory mechanisms of BCRP transporter. J Pharm Sci. 2019;108(3):1315–25.

    Article  CAS  Google Scholar 

  18. Homma M, Hirano T, Yuzawa K, Ohkochi N, Kenmochi T. Use trend for generic formulation of immunosuppressive agents: a questionnaire survey for clinical institution in Japan. Organ Boil. 2017;24(1):76–80.

    Google Scholar 

  19. Robertsen I, Åsberg A, Ingerø AO, Vethe NT, Bremer S, Bergan S, Midtvedt K. Use of generic tacrolimus in elderly renal transplant recipients: precaution is needed. Transplantation. 2015;99(3):528–32.

    Article  CAS  Google Scholar 

  20. Kimura N, Suzuki A, Sofue S. The bioequivalence between the original and the generic products of mycophenolate mofetil. Jpn Pharmacol Ther. 2015;43(7):945–54.

    CAS  Google Scholar 

  21. Crowe A. The influence of P-glycoprotein on morphine transport in Caco-2 cells. Comparison with Paclitaxel. Eur J Pharmacol. 2002;440(1):7–16.

    Article  CAS  Google Scholar 

  22. Saeki T, Ueda K, Tanigawara Y, Hori R, Komano T. Human P-glycoprotein transports cyclosporin A and FK506. J Biol Chem. 1993;268(9):6077–80.

    PubMed  CAS  Google Scholar 

  23. Tomita M, Ohkubo R, Hayashi M. Lipopolysaccharide transport system across colonic epithelial cells in normal and infective rat. Drug Metab Pharmacokinet. 2004;19(1):33–40.

    Article  CAS  Google Scholar 

  24. Mai Y, Dou L, Murdan S, Basit AW. An animal’s sex influences the effects of the excipient PEG 400 on the intestinal P-gp protein and mRNA levels, which has implications for oral drug absorption. Eur J Pharm Sci. 2018;120:53–60.

    Article  CAS  Google Scholar 

  25. Maruyama M, Ishida K, Watanabe Y, Nishikawa M, Takakura Y. Effects of methyl-beta-cyclodextrin treatment on secretion profile of interferon-beta and zonula occuludin-1 architecture in Madin-Darby canine kidney cell monolayers. Biol Pharm Bull. 2009;35:910–5.

    Article  Google Scholar 

  26. Sugibayashi K, Onuki Y, Takayama K. Displacement of tight junction proteins from detergent-resistant membrane domains by treatment with sodium caprate. Eur J Pharm Sci. 2009;36:246–53.

    Article  CAS  Google Scholar 

  27. Doi N, Tomita M, Hayashi M. Absorption enhancement effect of acylcarnitines through changes in tight junction protein in Caco-2 cell monolayers. Drug Metab Pharmacokinet. 2011;26:162–70.

    Article  CAS  Google Scholar 

  28. Pathak SM, Musmade P, Dengle S, Karthik A, Bhat K, Udupa N. Enhanced oral absorption of saquinavir with methyl-beta-cyclodextrin-preparation and in vitro and in vivo evaluation. Eur J Pharm Sci. 2010;41(3–4):440–51.

    Article  CAS  Google Scholar 

  29. Jouan E, Le Vee M, Denizot C, Da Violante G, Ferdel O. The mitochondrial fluorescent dye rhodamine 123 is a high-affinity substrate for organic cation transporters (OCTs) 1 and 2. Fundam Clin Pharmacol. 2014;28(1):65–77.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Mr. Yuki Aizawa and Mr. Daisuke Makie for their technical assistance.

Author information

Affiliations

  1. Division of Clinical Pharmaceutics, Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, 10281 Komuro, Ina-machi, Kitaadachi-gun, Saitama, 362-0806, Japan

    Yusuke Takizawa

  2. Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan

    Yusuke Takizawa, Nozomi Goto & Takahito Furuya

  3. Laboratory of Molecular Pharmaceutics and Technology, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki, Gunma, 370-0033, Japan

    Masahiro Hayashi

Authors
  1. Yusuke Takizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nozomi Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takahito Furuya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masahiro Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yusuke Takizawa.

Ethics declarations

Funding

This study was supported, in part, by a Grant-in-Aid for Young Scientists (B) (25860127) from the Japan Society for the Promotion of Sciences (JSPS).

Conflict of interest

The authors declare no conflicts of interest.

Ethics Approval

All animal experiments were performed according to the guidelines of the Tokyo University of Pharmacy and Life Sciences. The study was approved by the Tokyo University of Pharmacy and Life Sciences Committee on the Care and Use of Laboratory Animals (approval number: P12-65 and P13-42).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Takizawa, Y., Goto, N., Furuya, T. et al. Influene of Pharmaceutical Excipients on the Membrane Transport of a P-glycoprotein Substrate in the Rat Small Intestine. Eur J Drug Metab Pharmacokinet 45, 645–652 (2020). https://doi.org/10.1007/s13318-020-00631-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-020-00631-7