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 (IC 50 = 50 nM) and organic anion-transporting polypeptide 1B1 (OATP1B1; IC 50 > 10 mM), 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 (IC 50 ) 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 17b-glucuronide. Calculated parameters of maximum enterocyte concentration [I gut max ], maximum unbound hepatic inlet concentration, transporter fraction excreted value, and determined IC 50 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.

Investigating Transporter‐Mediated Drug‐Drug Interactions Using a Physiologically Based Pharmacokinetic Model of Rosuvastatin

“…In addition, rosuvastatin AUC and C max ratios from the simulations in which the intestinal BCRP was turned off compared with the current model were 2.99 and 3.47, respectively. These ratios are higher than the maximum predicted AUC ratio of two by Elsby et al . when the intestinal BCRP was assumed to be completedly inhibited.…”

“…In addition, rosuvastatin AUC and C max ratios from the simulations in which the intestinal BCRP was turned off compared with the current model were 2.99 and 3.47, respectively. These ratios are higher than the maximum predicted AUC ratio of two by Elsby et al 46 when the intestinal BCRP was assumed to be completedly inhibited. This difference was due to the inclusion of the intestinal influx transporter OST in the current model, thus the higher efflux by BCRP, as compared with the assumption by others that BCRP was the only transporter involved in rosuvastatin absorption.…”

Interaction betweenABCG2 421C>Apolymorphism and valproate in their effects on steady‐state disposition of lamotrigine in adults with epilepsy

“…Single nucleotide polymorphism of ABCG2 421C>A (p.Q141K) results in its reduced activity [44] -mRNA expression is maintained, but protein expression and function is reduced by 50-70% due to enhanced susceptibility to proteasomal degradation [45,46]. Variant allele carriage is associated with a higher systemic exposure to several statins and sulfasalazine [44,47] and with an increased incidence of adverse effects of statins [48,49] and gefitinib [50]. The present data suggest that it enhances the effect of valproate on exposure to lamotrigine.…”

Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information

“…By contrast, the pharmacokinetics of pitavastatin were affected by OATP1B1 polymorphism but not by BCRP polymorphism (Ieiri et al, 2007;Oh et al, 2013). Clopidogrel inhibits BCRP with an in vitro K i of 63 mM (Elsby et al, 2016). The maximum theoretical gastrointestinal concentration ([I g ]) of 300 mg clopidogrel can be calculated by dividing the dose [mol] by 250 ml, and was 3729 mM.…”