Skip to main content

Advertisement

SpringerLink
Log in

Lack of an Effect of Polysorbate 80 on Intestinal Drug Permeability in Humans

  • Original Research Article
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Despite no broad, direct evidence in humans, there is a potential concern that surfactants alter active or passive drug intestinal permeation to modulate oral drug absorption. The purpose of this study was to investigate the impact of the surfactant polysorbate 80 on active and passive intestinal drug absorption in humans.

Methods

The human (n = 12) pharmacokinetics (PK) of three probe substrates of intestinal absorption, valacyclovir, chenodeoxycholic acid (CDCA), and enalaprilat, were assessed. Endogenous bile acid levels were assessed as a secondary measure of transporter and microbiota impact.

Results

Polysorbate 80 did not inhibit peptide transporter 1 (PepT1)- or apical sodium bile acid transporter (ASBT)-mediated PK of valacyclovir and CDCA, respectively. Polysorbate 80 did not increase enalaprilat absorption. Modest increases in unconjugated secondary bile acid Cmax ratios suggest a potential alteration of the in vivo intestinal microbiota by polysorbate 80.

Conclusions

Polysorbate 80 did not alter intestinal membrane fluidity or cause intestinal membrane disruption. This finding supports regulatory relief of excipient restrictions for Biopharmaceutics Classification System-based biowaivers.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

AME:

Absorption-modifying excipient

ASBT:

Apical sodium bile acid transporter

BCS:

Biopharmaceutics Classification System

BE:

Bioequivalence

BID:

Twice a day

CDCA:

Chenodeoxycholic acid

CYP:

Cytochrome P450

EMA:

European Medicines Agency

FDA:

Food and Drug Administration

GMP:

Good Manufacturing Practice

ICH:

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use

Ki :

Inhibitory constant

MRP4:

Multidrug resistance protein 4

OCT1:

Organic cation transporter 1

PepT1:

Peptide transporter 1

P-gp:

P-glycoprotein

PK:

Pharmacokinetics

PKC:

Protein kinase C

WHO:

World Health Organization

References

  1. Zhang W, Li Y, Zou P, Wu M, Zhang Z, Zhang T. The Effects of Pharmaceutical Excipients on Gastrointestinal Tract Metabolic Enzymes and Transporters-an Update. AAPS J. 2016;18(4):830–43.

    Article  CAS  Google Scholar 

  2. Metry M, Polli JE. Evaluation of Excipient Risk in BCS Class I and III Biowaivers. AAPS J. 2022;24(1):20.

    Article  Google Scholar 

  3. Food and Drug Administration (FDA). Guidance for Industry: M9 Biopharmaceutics Classification System-Based Biowaivers. Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). May 2021.

  4. Vaithianathan S, Haidar SH, Zhang X, Jiang W, Avon C, Dowling TC, Shao C, Kane M, Hoag SW, Flasar MH, Ting TY, Polli JE. Effect of Common Excipients on the Oral Drug Absorption of Biopharmaceutics Classification System Class 3 Drugs Cimetidine and Acyclovir. J Pharm Sci. 2016;105(2):996–1005.

    Article  CAS  Google Scholar 

  5. Food and Drug Administration (FDA). Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. Center for Drug Evaluation and Research (CDER). 2017

  6. Rege BD, Kao JP, Polli JE. Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur J Pharm Sci. 2002;16(4–5):237–46.

    Article  CAS  Google Scholar 

  7. Rege BD, Yu LX, Hussain AS, Polli JE. Effect of common excipients on Caco-2 transport of low-permeability drugs. J Pharm Sci. 2001;90(11):1776–86.

    Article  CAS  Google Scholar 

  8. Chassaing B, Koren O, Goodrich JK, Poole AC, Srinivasan S, Ley RE, Gewirtz AT. Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome. Nature. 2015;519(7541):92–6.

    Article  CAS  Google Scholar 

  9. Otter M, Oswald S, Siegmund W, Keiser M. Effects of frequently used pharmaceutical excipients on the organic cation transporters 1–3 and peptide transporters 1/2 stably expressed in MDCKII cells. Eur J Pharm Biopharm. 2017;112:187–95.

    Article  CAS  Google Scholar 

  10. Stieger B, Steiger J, Locher KP. Membrane lipids and transporter function. Biochim Biophys Acta (BBA) - Mol Basis of Dis. 2021;1867(5):166079.

  11. Dudeja PK, Anderson KM, Harris JS, Buckingham L, Coon JS. Reversal of Multidrug-Resistance Phenotype by Surfactants: Relationship to Membrane Lipid Fluidity. Arch Biochem Biophys. 1995;319(1):309–15.

    Article  CAS  Google Scholar 

  12. Woodcock DM, Linsenmeyer ME, Chojnowski G, Kriegler AB, Nink V, Webster LK, Sawyer WH. Reversal of multidrug resistance by surfactants. Br J Cancer. 1992;66(1):62–8.

    Article  CAS  Google Scholar 

  13. Sarwar Z, Annaba F, Dwivedi A, Saksena S, Gill RK, Alrefai WA. Modulation of ileal apical Na+-dependent bile acid transporter ASBT by protein kinase C. Am J Physiol Gastrointest Liver Physiol. 2009;297(3):G532-538.

    Article  CAS  Google Scholar 

  14. Zhao F-K, Chuang LF, Israel M, Chuang RY. Cremophor EL, a widely used parenteral vehicle, is a potent inhibitor of protein kinase C. Biochem Biophys Res Commun. 1989;159(3):1359–67.

    Article  CAS  Google Scholar 

  15. Tompkins L, Lynch C, Haidar S, Polli J, Wang H. Effects of commonly used excipients on the expression of CYP3A4 in colon and liver cells. Pharm Res. 2010;27(8):1703–12.

    Article  CAS  Google Scholar 

  16. Mountfield RJ, Senepin S, Schleimer M, Walter I, Bittner B. Potential inhibitory effects of formulation ingredients on intestinal cytochrome P450. Int J Pharm. 2000;211(1):89–92.

    Article  CAS  Google Scholar 

  17. Naimi S, Viennois E, Gewirtz AT, Chassaing B. Direct impact of commonly used dietary emulsifiers on human gut microbiota. Microbiome. 2021;9(1):66.

    Article  CAS  Google Scholar 

  18. Alam A, Neish A. Role of gut microbiota in intestinal wound healing and barrier function. Tissue barriers. 2018;6(3):1539595–1539595.

    Article  Google Scholar 

  19. Yang B, Smith DE. Significance of peptide transporter 1 in the intestinal permeability of valacyclovir in wild-type and PepT1 knockout mice. Drug Metab Dispos. 2013;41(3):608–14.

    Article  CAS  Google Scholar 

  20. Ganapathy ME, Huang W, Wang H, Ganapathy V, Leibach FH. Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2. Biochem Biophys Res Commun. 1998;246(2):470–5.

    Article  CAS  Google Scholar 

  21. Dawson PA. Role of the intestinal bile acid transporters in bile acid and drug disposition. Handb Exp Pharmacol. 2011;201:169–203.

    Article  CAS  Google Scholar 

  22. Kubo SH, Cody RJ. Clinical pharmacokinetics of the angiotensin converting enzyme inhibitors. A review Clin Pharmacokinet. 1985;10(5):377–91.

    Article  CAS  Google Scholar 

  23. Pravachol [package insert]. Princeton, NJ: Bristol-Myers Squibb. 2016.

  24. Chenodal [package insert]. San Diego, CA: Retrophin, Inc. 2020.

  25. Enalaprilat Injection [package insert]. Lake Forest, IL: Hospira, Inc. 2018.

  26. Valtrex (valacyclovir) [package insert]. Research Triangle Park, NC: GlaxoSmithKline. 2008.

  27. IBM Watson Health. Drug interactions: Pravastatin, Chenodiol, Enalaprilat, & Valacyclovir. In.: IBM Micromedex: Drug Interaction Checking [Electronic version]. Retrieved March 8, 2022, from https://www.micromedexsolutions.com/; 2022.

  28. Pravastatin, Chenodiol, Enalaprilat, & Valacyclovir. In.: Lexicomp: Interactions [Electronic version]. Hudson, Ohio: Wolters Kluwer UpToDate, Inc., 2022. Retrieved March 8, 2022, from http://online.lexi.com; 2022.

  29. Food and Drug Administration (FDA). Inactive Ingredient Database (IID). Center for Drug Evaluation and Research (CDER). 2022.

  30. Sandoval PJ, Zorn KM, Clark AM, Ekins S, Wright SH. Assessment of Substrate-Dependent Ligand Interactions at the Organic Cation Transporter OCT2 Using Six Model Substrates. Mol Pharmacol. 2018;94(3):1057–68.

    Article  CAS  Google Scholar 

  31. Russo DP, Zorn KM, Clark AM, Zhu H, Ekins S. Comparing Multiple Machine Learning Algorithms and Metrics for Estrogen Receptor Binding Prediction. Mol Pharm. 2018;15(10):4361–70.

    Article  CAS  Google Scholar 

  32. U.S. Food and Drug Administration. Bioanalytical Method Validation. Guidance for Industry (2018).

  33. Shiffka SJ, Jones JW, Li L, Farese AM, MacVittie TJ, Wang H, Swaan PW, Kane MA. Quantification of common and planar bile acids in tissues and cultured cells. J Lipid Res. 2020;61(11):1524–35.

    Article  CAS  Google Scholar 

  34. Gu H, Liu G, Wang J, Aubry A-F, Arnold ME. Selecting the Correct Weighting Factors for Linear and Quadratic Calibration Curves with Least-Squares Regression Algorithm in Bioanalytical LC-MS/MS Assays and Impacts of Using Incorrect Weighting Factors on Curve Stability, Data Quality, and Assay Performance. Anal Chem. 2014;86(18):8959–66.

    Article  CAS  Google Scholar 

  35. Soul-Lawton J, Seaber E, On N, Wootton R, Rolan P, Posner J. Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans. Antimicrob Agents Chemother. 1995;39(12):2759–64.

    Article  CAS  Google Scholar 

  36. Zovirax (acyclovir) [package insert]. Research Triangle Park, NC: GlaxoSmithKline. 2005.

  37. Dawson PA, Lan T, Rao A. Bile acid transporters. J Lipid Res. 2009;50(12):2340–57.

    Article  CAS  Google Scholar 

  38. Balakrishnan A, Wring SA, Polli JE. Interaction of native bile acids with human apical sodium-dependent bile acid transporter (hASBT): influence of steroidal hydroxylation pattern and C-24 conjugation. Pharm Res. 2006;23(7):1451–9.

    Article  CAS  Google Scholar 

  39. Tolle-Sander S, Lentz KA, Maeda DY, Coop A, Polli JE. Increased acyclovir oral bioavailability via a bile acid conjugate. Mol Pharm. 2004;1(1):40–8.

    Article  CAS  Google Scholar 

  40. Zheng X, Ekins S, Raufman JP, Polli JE. Computational models for drug inhibition of the human apical sodium-dependent bile acid transporter. Mol Pharm. 2009;6(5):1591–603.

    Article  CAS  Google Scholar 

  41. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.

    Article  CAS  Google Scholar 

  42. Verbeeck RK, Kanfer I, Lobenberg R, Abrahamsson B, Cristofoletti R, Groot DW, Langguth P, Polli JE, Parr A, Shah VP, Mehta M, Dressman JB. Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Enalapril. J Pharm Sci. 2017;106(8):1933–43.

    Article  CAS  Google Scholar 

  43. Lennernäs H. Intestinal permeability and its relevance for absorption and elimination. Xenobiotica. 2007;37(10–11):1015–51.

    Article  Google Scholar 

  44. Swaan PW, Stehouwer MC, Tukker JJ. Molecular mechanism for the relative binding affinity to the intestinal peptide carrier. Comparison of three ACE-inhibitors: enalapril, enalaprilat, and lisinopril. Biochim Biophys Acta. 1995;1236(1):31–38.

  45. Balakrishnan A, Wring SA, Coop A, Polli JE. Influence of charge and steric bulk in the C-24 region on the interaction of bile acids with human apical sodium-dependent bile acid transporter. Mol Pharm. 2006;3(3):282–92.

    Article  CAS  Google Scholar 

  46. Lin CJ, Akarawut W, Smith DE. Competitive inhibition of glycylsarcosine transport by enalapril in rabbit renal brush border membrane vesicles: interaction of ACE inhibitors with high-affinity H+/peptide symporter. Pharm Res. 1999;16(5):609–15.

    Article  CAS  Google Scholar 

  47. Poland JC, Flynn CR. Bile Acids, Their Receptors, and the Gut Microbiota. Physiology. 2021;36(4):235–45.

    Article  CAS  Google Scholar 

  48. Cook JA, Davit BM, Polli JE. Impact of Biopharmaceutics Classification System-Based Biowaivers. Mol Pharm. 2010;7(5):1539–44.

    Article  CAS  Google Scholar 

  49. García-Arieta A. Interactions between active pharmaceutical ingredients and excipients affecting bioavailability: impact on bioequivalence. Eur J Pharm Sci. 2014;65:89–97.

    Article  Google Scholar 

  50. van Os S, Relleke M, Piniella PM. Lack of bioequivalence between generic risperidone oral solution and originator risperidone tablets. Int J Clin Pharmacol Ther. 2007;45(5):293–9.

    Article  Google Scholar 

  51. Sjögren E, Abrahamsson B, Augustijns P, Becker D, Bolger MB, Brewster M, Brouwers J, Flanagan T, Harwood M, Heinen C, Holm R, Juretschke HP, Kubbinga M, Lindahl A, Lukacova V, Münster U, Neuhoff S, Nguyen MA, Peer A, Reppas C, Hodjegan AR, Tannergren C, Weitschies W, Wilson C, Zane P, Lennernäs H, Langguth P. In vivo methods for drug absorption - comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects. Eur J Pharm Sci. 2014;57:99–151.

    Article  Google Scholar 

  52. Parr A, Hidalgo IJ, Bode C, Brown W, Yazdanian M, Gonzalez MA, Sagawa K, Miller K, Jiang W, Stippler ES. The Effect of Excipients on the Permeability of BCS Class III Compounds and Implications for Biowaivers. Pharm Res. 2016;33(1):167–76.

    Article  CAS  Google Scholar 

  53. Dahlgren D, Roos C, Lundqvist A, Tannergren C, Langguth P, Sjöblom M, Sjögren E, Lennernäs H. Preclinical Effect of Absorption Modifying Excipients on Rat Intestinal Transport of Model Compounds and the Mucosal Barrier Marker 51Cr-EDTA. Mol Pharm. 2017;14(12):4243–51.

    Article  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

Ms. Kimberley Zorn and Dr. Alex Clark are acknowledged for assistance with computational models. All authors declared no competing interests for this work.

Funding

This work was funded by the generosity of Marilyn Shangraw. JEP is the Ralph F. Shangraw Endowed Professor in Industrial Pharmacy and Pharmaceutics. We acknowledge the support of the University of Maryland, Baltimore, Institute for Clinical & Translational Research (ICTR) and the National Center for Advancing Translational Sciences (NCATS) Clinical Translational Science Award (CTSA) grant number 1UL1TR003098. The machine learning work was supported by National Institutes of Health National Institute of General Medical Sciences grant R44GM122196. Additional support was provided by the University of Maryland School of Pharmacy Mass Spectrometry Center (SOP1841-IQB2014).

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland, N62321201, USA

    Melissa Metry, Samuel A. Krug, Vijaya Kumari Karra, Stephen W. Hoag, Maureen A. Kane & James E. Polli

  2. Collaborations Pharmaceuticals, Inc, Raleigh, North Carolina, USA

    Sean Ekins

  3. Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA

    Jeffrey C. Fink

Authors
  1. Melissa Metry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samuel A. Krug
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vijaya Kumari Karra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sean Ekins
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen W. Hoag
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maureen A. Kane
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jeffrey C. Fink
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. James E. Polli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James E. Polli.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 890 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Metry, M., Krug, S.A., Karra, V.K. et al. Lack of an Effect of Polysorbate 80 on Intestinal Drug Permeability in Humans. Pharm Res 39, 1881–1890 (2022). https://doi.org/10.1007/s11095-022-03312-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-022-03312-z

KEY WORDS

Search

Navigation