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Research ArticleArticle

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

Robert Elsby, Paul Martin, Dominic Surry, Pradeep Sharma and Katherine Fenner
Drug Metabolism and Disposition March 2016, 44 (3) 398-408; DOI: https://doi.org/10.1124/dmd.115.066795
Robert Elsby
DMPK, Drug Safety and Metabolism (R.E., D.S.), and Quantitative Clinical Pharmacology, (P.M.), AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, United Kingdom; and DMPK, Drug Safety and Metabolism, AstraZeneca R&D Darwin, Cambridge, Cambridgeshire, United Kingdom (P.S., K.F.)
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Paul Martin
DMPK, Drug Safety and Metabolism (R.E., D.S.), and Quantitative Clinical Pharmacology, (P.M.), AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, United Kingdom; and DMPK, Drug Safety and Metabolism, AstraZeneca R&D Darwin, Cambridge, Cambridgeshire, United Kingdom (P.S., K.F.)
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Dominic Surry
DMPK, Drug Safety and Metabolism (R.E., D.S.), and Quantitative Clinical Pharmacology, (P.M.), AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, United Kingdom; and DMPK, Drug Safety and Metabolism, AstraZeneca R&D Darwin, Cambridge, Cambridgeshire, United Kingdom (P.S., K.F.)
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Pradeep Sharma
DMPK, Drug Safety and Metabolism (R.E., D.S.), and Quantitative Clinical Pharmacology, (P.M.), AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, United Kingdom; and DMPK, Drug Safety and Metabolism, AstraZeneca R&D Darwin, Cambridge, Cambridgeshire, United Kingdom (P.S., K.F.)
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Katherine Fenner
DMPK, Drug Safety and Metabolism (R.E., D.S.), and Quantitative Clinical Pharmacology, (P.M.), AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, United Kingdom; and DMPK, Drug Safety and Metabolism, AstraZeneca R&D Darwin, Cambridge, Cambridgeshire, United Kingdom (P.S., K.F.)
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Abstract

The intestinal efflux transporter breast cancer resistance protein (BCRP) restricts the absorption of rosuvastatin. Of the transporters important to rosuvastatin disposition, fostamatinib inhibited BCRP (IC50 = 50 nM) and organic anion-transporting polypeptide 1B1 (OATP1B1; IC50 > 10 μM), but not organic anion transporter 3, in vitro, predicting a drug-drug interaction (DDI) in vivo through inhibition of BCRP only. Consequently, a clinical interaction study between fostamatinib and rosuvastatin was performed (and reported elsewhere). This confirmed the critical role BCRP plays in statin absorption, as inhibition by fostamatinib resulted in a significant 1.96-fold and 1.88-fold increase in rosuvastatin area under the plasma concentration–time curve (AUC) and Cmax, respectively. An in vitro BCRP inhibition assay, using polarized Caco-2 cells and rosuvastatin as probe substrate, was subsequently validated with literature inhibitors and used to determine BCRP inhibitory potencies (IC50) of the perpetrator drugs eltrombopag, darunavir, lopinavir, clopidogrel, ezetimibe, fenofibrate, and fluconazole. OATP1B1 inhibition was also determined using human embryonic kidney 293–OATP1B1 cells versus estradiol 17β-glucuronide. Calculated parameters of maximum enterocyte concentration [Igut max], maximum unbound hepatic inlet concentration, transporter fraction excreted value, and determined IC50 value were incorporated into mechanistic static equations to compute theoretical increases in rosuvastatin AUC due to inhibition of BCRP and/or OATP1B1. Calculated theoretical increases in exposure correctly predicted the clinically observed changes in rosuvastatin exposure and suggested intestinal BCRP inhibition (not OATP1B1) to be the mechanism underlying the DDIs with these drugs. In conclusion, solitary inhibition of the intestinal BCRP transporter can result in clinically significant DDIs with rosuvastatin, causing up to a maximum 2-fold increase in exposure, which may warrant statin dose adjustment in clinical practice.

Footnotes

    • Received August 13, 2015.
    • Accepted December 18, 2015.
  • ↵1 Current affiliation: Drug Transporter Services, Cyprotex Discovery Ltd., Biohub at Alderley Park, Macclesfield, Cheshire, United Kingdom.

  • ↵2 Current affiliation (DS): Skill Supply, Sandbach, Cheshire, United Kingdom.

  • This research was funded by AstraZeneca. P.M., P.S., and K.F. are employees of AstraZeneca, and R.E. and D.S. are former employees of AstraZeneca.

  • dx.doi.org/10.1124/dmd.115.066795.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (3)
Drug Metabolism and Disposition
Vol. 44, Issue 3
1 Mar 2016
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Research ArticleArticle

Inhibition of Intestinal BCRP Increases Rosuvastatin Exposure

Robert Elsby, Paul Martin, Dominic Surry, Pradeep Sharma and Katherine Fenner
Drug Metabolism and Disposition March 1, 2016, 44 (3) 398-408; DOI: https://doi.org/10.1124/dmd.115.066795

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Research ArticleArticle

Inhibition of Intestinal BCRP Increases Rosuvastatin Exposure

Robert Elsby, Paul Martin, Dominic Surry, Pradeep Sharma and Katherine Fenner
Drug Metabolism and Disposition March 1, 2016, 44 (3) 398-408; DOI: https://doi.org/10.1124/dmd.115.066795
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