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.