European Journal of Clinical Pharmacology

, Volume 72, Issue 8, pp 925–931 | Cite as

No effects of pantoprazole on the pharmacokinetics of rosuvastatin in healthy subjects

  • J. Huguet
  • J. Lu
  • F. Gaudette
  • J.-L. Chiasson
  • P. Hamet
  • V. Michaud
  • J. TurgeonEmail author
Clinical Trial



Rosuvastatin disposition is modulated by the expression and activity of several membrane transporters including BCRP (ABCG2). The objective of our study was to investigate the effects of pantoprazole, a previously proposed BCRP inhibitor, on the disposition of rosuvastatin.


The impact of pantoprazole (40 mg ID for 2 days) on rosuvastatin pharmacokinetics was evaluated in healthy volunteers (n = 16) who received a single oral dose of rosuvastatin (10 mg) either alone or with pantoprazole. Rosuvastatin, N-desmethylrosuvastatin, and rosuvastatin lactone levels were quantified in plasma while rosuvastatin and N-desmethylrosuvastatin excretion were measured in urine.


Ratios and 90 % standard confidence interval of geometric means for C max (1.03 [0.91–1.16]), AUC0–∞ (1.03 [0.89–1.19]) and renal clearance (0.96 [0.85–1.09]) were all within the pre-specified range of 0.8–1.25, indicating a lack of drug-drug interaction between pantoprazole and rosuvastatin.


Concomitant administration of pantoprazole with rosuvastatin did not affect rosuvastatin plasma concentrations. The use of pantoprazole as a BCRP inhibitor should be revisited when characterizing BCRP-mediated transport in humans.


Rosuvastatin Pantoprazole BCRP ABCG2 Transporters Pharmacokinetics Drug interaction 



We acknowledge the contribution of Ms. Suzanne Dallaire, Ms. Hélène Langelier, and Ms. Suzanne Bordeleau (Research Group on Diabetes and Metabolic Regulation, CRCHUM Department of Medicine, Université de Montréal, Montréal, Quebec, Canada). We also acknowledge the contribution of Ms. Jocelyne Doucet and Ms. Mélissa Nelson.

This project was supported by internal funding obtained from the Fondation du CHUM. Jade Huguet was subsequently the recipient of a studentship from the Canadian Institutes of Health Research (CIHR) and the Fonds de Recherche Santé Québec (FRSQ). Jennifer Lu is the recipient of a studentship from the Fonds de Recherche Santé Québec (FRSQ). Veronique Michaud is the recipient of a research scholarship from FRQS in partnership with the Institut national d’excellence en santé et en services sociaux (INESSS).

Author contributions

Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work: Huguet J., Lu J., Gaudette F., Chiasson J.-L., Hamet P., Michaud V., Turgeon J.

Drafting the work or revising it critically for important intellectual content: Huguet J., Gaudette F., Chiasson J.-L., Hamet P., Michaud V., Turgeon J.

Final approval of the version to be published: Huguet J., Lu J., Gaudette F., Chiasson J.-L., Hamet P., Michaud V., Turgeon J.

Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: Huguet J., Lu J., Gaudette F., Chiasson J.-L., Hamet P., Michaud V., Turgeon J.

Compliance with ethical standards

The project was approved by the Ethic Committee of the CHUM Research Center (Trial #09.252), University of Montreal and the competent authority in Canada (Control Number #138105). Informed consent was obtained from all individual participants included in the study.

Disclosure of potential conflicts of interest

All authors have completed the Unified Competing Interest form at and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years ; no other relationships or activities that could appear to have influenced the submitted work.

Supplementary material

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Supplemental Figure 1

Inhibition kinetics of pantoprazole (inhibitor) on rosuvastatin efflux transport in BCRP vesicles. Pantoprazole concentrations were 3–50 μM. The IC50 value is 20.9 μM. The values in parentheses represent the 95 % confidence interval. Method: Rosuvastatin Transport in Membrane Vesicles. Frozen membrane vesicles were thawed in a 25 °C water bath. A protein content of 25 μg were used in the inhibition studies. All incubations were conducted under agitation at 400 rpm in a thermomixer. The membrane vesicles were pre-incubated for 10 min at 37 °C in a Tris-sucrose buffer (250 mM sucrose, 10 mM Tris, 10 mM MgCl2, pH 7.0) containing rosuvastatin 50 μM and increasing concentrations of pantoprazole (0–50 μM). Uptake was initiated by adding Mg-ATP 3 mM. After 2 min, the reaction was stopped by addition of 200 μl ice-cold wash buffer (10 mM Tris-HCl, 250 mM sucrose, 100 mM NaCl, pH 7.0). The samples were transferred to a 96-well filterplate (AcroPrep™ 96 Filter Plate, 3 μm Glass/0.2 μm BioInert; Pall Corporation) and the vesicles were isolated by rapid filtration. The vesicles were washed with 200 μl of ice-cold wash buffer five times. Samples were mixed in scintillation counting cocktail (5 mL; Bio-Safe II, Research Products International Corp.) to measure intracellular radioactivity (LSC 1600TR, Packard) (JPEG 42.5 kb).

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  1. 1.
    Carswell CI, Plosker GL, Jarvis B (2002) Rosuvastatin. Drugs 62(14):2075–2085CrossRefPubMedGoogle Scholar
  2. 2.
    Martin PD, Warwick MJ, Dane AL, Brindley C, Short T (2003) Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers. Clin Ther 25(10):2553–2563CrossRefPubMedGoogle Scholar
  3. 3.
    Kitamura S, Maeda K, Wang Y, Sugiyama Y (2008) Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos 36(10):2014–2023CrossRefPubMedGoogle Scholar
  4. 4.
    Schneck DW, Birmingham BK, Zalikowski JA, Mitchell PD, Wang Y, Martin PD, Lasseter KC, Brown CDA, Windass AS, Raza A (2004) The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther 75(5):455–463CrossRefPubMedGoogle Scholar
  5. 5.
    Ho RH, Kim RB (2005) Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther 78(3):260–277CrossRefPubMedGoogle Scholar
  6. 6.
    Bergman E, Forsell P, Tevell A, Persson EM, Hedeland M, Bondesson U, Knutson L, Lennernäs H (2006) Biliary secretion of rosuvastatin and bile acids in humans during the absorption phase. Eur J Pharm Sci 29(3–4):205–214CrossRefPubMedGoogle Scholar
  7. 7.
    Kalliokoski A, Niemi M (2009) Impact of OATP transporters on pharmacokinetics. Br J Pharmacol 158(3):693–705CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ho RH, Tirona RG, Leake BF, Glaeser H, Lee W, Lemke CJ, Wang Y, Kim RB (2006) Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology 130(6):1793–1806CrossRefPubMedGoogle Scholar
  9. 9.
    Varma MV, Rotter CJ, Chupka J, Whalen KM, Duignan DB, Feng B, Litchfield J, Goosen TC, El-Kattan AF (2011) pH-sensitive interaction of HMG-CoA reductase inhibitors (statins) with organic anion transporting polypeptide 2B1. Mol Pharm 8(4):1303–1313CrossRefPubMedGoogle Scholar
  10. 10.
    Simonson SG, Raza A, Martin PD, Mitchell PD, Jarcho JA, Brown CDA, Windass AS, Schneck DW (2004) Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clin Pharmacol Ther 76(2):167–177CrossRefPubMedGoogle Scholar
  11. 11.
    Keskitalo JE, Zolk O, Fromm MF, Kurkinen KJ, Neuvonen PJ, Niemi M (2009) ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 86(2):197–203CrossRefPubMedGoogle Scholar
  12. 12.
    Huang L, Wang Y, Grimm S (2006) ATP-dependent transport of rosuvastatin in membrane vesicles expressing breast cancer resistance protein. Drug Metab Dispos 34(5):738–742CrossRefPubMedGoogle Scholar
  13. 13.
    Elsby R, Martin P, Surry D, Sharma P, Fenner K (2016) Solitary inhibition of the breast cancer resistance protein efflux transporter results in a clinically significant drug-drug interaction with rosuvastatin by causing up to a 2-fold increase in statin exposure. Drug Metab Dispos 44(3):398–408CrossRefPubMedGoogle Scholar
  14. 14.
    Camenish G, Riede J, Kunze A, Huwyler J, Poller B, Umehara K (2015) The extended clearance model and its use for the interpretation of hepatobiliary elimination data. ADMET & DMPK 3(1):1–14Google Scholar
  15. 15.
    Pham PA, la Porte CJL, Lee LS, van Heeswijk R, Sabo JP, Elgadi MM, Piliero PJ, Barditch-Crovo P, Fuchs E, Flexner C, Cameron DW (2009) Differential effects of tipranavir plus ritonavir on atorvastatin or rosuvastatin pharmacokinetics in healthy volunteers. Antimicrob Agents Chemother 53(10):4385–4392CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kiser JJ, Gerber JG, Predhomme JA, Wolfe P, Flynn DM, Hoody DW (2008) Drug/drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr 47(5):570–578CrossRefPubMedGoogle Scholar
  17. 17.
    Busti AJ, Bain AM, Hall RGI, Bedimo RG, Leff RD, Meek C, Mehvar R (2008) Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol 51(6):605–610CrossRefPubMedGoogle Scholar
  18. 18.
    Lee E, Ryan S, Birmingham B, Zalikowski J, March R, Ambrose H, Moore R, Lee C, Chen Y, Schneck D (2005) Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther 78(4):330–341CrossRefPubMedGoogle Scholar
  19. 19.
    Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M (2007) Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 82(6):726–733CrossRefPubMedGoogle Scholar
  20. 20.
    Romaine SPR, Bailey KM, Hall AS, Balmforth AJ (2009) The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy. Pharm J 10(1):1–11Google Scholar
  21. 21.
    Tomlinson B, Hu M, Lee VWY, Lui SSH, Chu TTW, Poon EWM, Ko GTC, Baum L, Tam LS, Li EK (2010) ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin. Clin Pharmacol Ther 87(5):558–562CrossRefPubMedGoogle Scholar
  22. 22.
    Zhang W, Yu B-N, He Y-J, Fan L, Li Q, Liu Z-Q, Wang A, Liu Y-L, Tan Z-R, Fen J, Huang Y-F, Zhou H-H (2006) Role of BCRP 421C > A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. Clin Chim Acta 373(1–2):99–103CrossRefPubMedGoogle Scholar
  23. 23.
    Suzuki K, Doki K, Homma M, Tamaki H, Hori S, Ohtani H, Sawada Y, Kohda Y (2009) Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy. Br J Clin Pharmacol 67(1):44–49CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kunze A, Poller B, Huwyler J, Camenisch G (2015) Application of the extended clearance concept classification system (ECCCS) to predict the victim drug-drug interaction potential of statins. Drug Metab Personalized Ther 30(3):175–188CrossRefGoogle Scholar
  25. 25.
    Martin PD, Warwick MJ, Dane AL, Hill SJ, Giles PB, Phillips PJ, Lenz E (2003) Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clin Ther 25(11):2822–2835CrossRefPubMedGoogle Scholar
  26. 26.
    Elsby R, Hilgendorf C, Fenner K (2012) Understanding the critical disposition pathways of statins to assess drug–drug interaction risk during drug development: it’s not just about OATP1B1. Clin Pharmacol Ther 92(5):584–598CrossRefPubMedGoogle Scholar
  27. 27.
    Agarwal S, Arya V, Zhang L (2013) Review of P-gp inhibition data in recently approved new drug applications: utility of the proposed [I1]/IC50 and [I2]/IC50 criteria in the P-gp decision tree. J Clin Pharmacol 53(2):228–233CrossRefPubMedGoogle Scholar
  28. 28.
    Tiberg M, Dudley A, Ungell A (2004) Regional and pH dependent permeability of rosuvastatin. In: AAPS 2004ed. AAPS journal, pp, T 2202.Google Scholar
  29. 29.
    Nakayama T, Maeda K, Fukizawa S, Kato Y, Dawson PA, Kusuhara H (2014) Characterization of the secretory transport of drugs in the mouse small intestine using Ussing chamber system. In: 19th North American ISSX 2014 (International Society for the Study of Xenobiotics) ed. International Society for the Study of Xenobiotics, pp, P 16.Google Scholar
  30. 30.
    Masubuchi N, Yamazaki H, Tanaka M (1998) Stereoselective chiral inversion of pantoprazole enantiomers after separate doses to rats. Chirality 10(8):747–753CrossRefPubMedGoogle Scholar
  31. 31.
    Kusuhara H, Sugiyama Y (2009) In vitro-in vivo extrapolation of transporter-mediated clearance in the liver and kidney. Drug Metab Pharmacokinet 24(1):37–52CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • J. Huguet
    • 1
    • 2
  • J. Lu
    • 1
  • F. Gaudette
    • 1
  • J.-L. Chiasson
    • 1
    • 3
    • 4
  • P. Hamet
    • 1
    • 3
    • 4
  • V. Michaud
    • 1
    • 2
    • 4
  • J. Turgeon
    • 1
    • 2
    • 3
    • 4
    • 5
    Email author
  1. 1.CRCHUMCentre de recherche du Centre hospitalier de l’Université de de MontréalMontréalCanada
  2. 2.Faculty of PharmacyUniversity of MontrealMontrealCanada
  3. 3.Faculty of MedicineUniversity of MontrealMontrealCanada
  4. 4.Research Group on Diabetes and Metabolic RegulationCRCHUMMontrealCanada
  5. 5.Tabula Rasa HealthcareMoorestownUSA

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