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

被引:83
作者
Elsby, Robert [1 ,4 ]
Martin, Paul [2 ]
Surry, Dominic [1 ,5 ]
Sharma, Pradeep [3 ]
Fenner, Katherine [3 ]
机构
[1] AstraZeneca R&D Alderley Pk, DMPK Drug Safety & Metab, Macclesfield, Cheshire, England
[2] AstraZeneca R&D Alderley Pk, Quantitat Clin Pharmacol, Macclesfield, Cheshire, England
[3] AstraZeneca R&D Darwin, DMPK Drug Safety & Metab, Cambridge CB4 0WG, Cambs, England
[4] Cyprotex Discovery Ltd, Drug Transporter Serv, Biohub, Alderley Pk, Macclesfield, Cheshire, England
[5] Skill Supply, Sandbach, Cheshire, England
关键词
SUPPORT REGULATORY SUBMISSIONS; TYROSINE KINASE INHIBITOR; IN-VITRO; P-GLYCOPROTEIN; PHARMACOKINETIC INTERACTIONS; HEALTHY-VOLUNTEERS; INTERACTION RISK; ASIAN SUBJECTS; HEPATIC-UPTAKE; ABCG2;
D O I
10.1124/dmd.115.066795
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 mu M), 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 C-max, 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 17 beta-glucuronide. Calculated parameters of maximum enterocyte concentration [I-gut 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.
引用
收藏
页码:398 / 408
页数:11
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