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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. 2016 Mar; 44(3):398-408.DM

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.

Authors+Show Affiliations

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.).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.).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.).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.).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.) Katherine.Fenner@astrazeneca.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26700956

Citation

Elsby, Robert, et al. "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 Metabolism and Disposition: the Biological Fate of Chemicals, vol. 44, no. 3, 2016, pp. 398-408.
Elsby R, Martin P, Surry D, et al. 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. 2016;44(3):398-408.
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 Metabolism and Disposition: the Biological Fate of Chemicals, 44(3), 398-408. https://doi.org/10.1124/dmd.115.066795
Elsby R, et al. 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. 2016;44(3):398-408. PubMed PMID: 26700956.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Elsby,Robert, AU - Martin,Paul, AU - Surry,Dominic, AU - Sharma,Pradeep, AU - Fenner,Katherine, Y1 - 2015/12/23/ PY - 2015/08/13/received PY - 2015/12/18/accepted PY - 2015/12/25/entrez PY - 2015/12/25/pubmed PY - 2016/10/25/medline SP - 398 EP - 408 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 44 IS - 3 N2 - 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. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/26700956/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_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=26700956 DB - PRIME DP - Unbound Medicine ER -