title: 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.
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.affiliation: 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.).
authors.forename: Robert
authors.initials: R
authors.lastname: Elsby
authors.affiliation: 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.).
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.affiliation: 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.).
authors.forename: Dominic
authors.initials: D
authors.lastname: Surry
authors.affiliation: 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.).
authors.forename: Pradeep
authors.initials: P
authors.lastname: Sharma
authors.affiliation: 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.
authors.forename: Katherine
authors.initials: K
authors.lastname: Fenner
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000631:Aminopyridines; D019540:Area Under Curve; D001692:Biological Transport / Q000187:drug effects*; D018938:Caco-2 Cells; D004347:Drug Interactions / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D007408:Intestinal Absorption / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins / Q000378:metabolism; D009025:Morpholines; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism; D010078:Oxazines / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism*; D011743:Pyrimidines; D000068718:Rosuvastatin Calcium / Q000378:metabolism*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000631:Aminopyridines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins; D009025:Morpholines; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; C503999:SLCO1B1 protein, human; D000068718:Rosuvastatin Calcium; C523665:fostamatinib