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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

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Rosuvastatin Pantoprazole BCRP ABCG2 Transporters Pharmacokinetics Drug interaction 

Notes

Acknowledgments

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 http://www.icmje.org/coi_disclosure.pdf 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

228_2016_2065_Fig6_ESM.jpg (43 kb)
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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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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