Significance of gut breast cancer resistance protein versus organic anion transporting polypeptide 2B1 inhibition on rosuvastatin clinical drug-drug interactions.

Organic anion transporting polypeptide (OATP)2B1 facilitates oral absorption of many drugs including celiprolol, fexofenadine, and rosuvastatin. The present study aimed to examine the relevance of gut OATP2B1 and breast cancer resistance protein (BCRP) inhibition in rosuvastatin drug-drug interactions (DDIs). We first characterized OATP2B1-mediated transport of rosuvastatin in transfected cells as a function of extracellular pH 6.0 and 7.4. Rosuvastatin transporter-specific uptake was found to be pH sensitive with 2-fold higher Vmax at acidic pH; however, OATP2B1 affinity (Km = 8-10 μM) was similar at both conditions. We next studied the effect of 26 inhibitor drugs on rosuvastatin OATP2B1-specific transport at 2 pH conditions. Measured IC50s were generally consistent between the 2 pHs (∼88% with 2-fold). For an additional 23 drugs, OATP2B1 IC50 was obtained only at pH 7.4 due to observed limited pH dependency. Inhibition of BCRP-mediated rosuvastatin transport was also acquired at pH 7.4 for 40 compounds using membrane vesicles assay. Finally, the static model for gut interactions (G-value, I2/IC50) was employed to project in vivo DDI potential. A significant relationship was observed between the BCRP G-value and rosuvastatin area under the curve (AUC) ratio; however, no correlation was apparent with the OATP2B1 G-value. The majority of inhibitors with BCRP G-values >100 perpetrated a "positive" DDI (AUC ratio >1.25). Ronacaleret and elagolix reduced rosuvastatin AUC by 40%-50%, likely due to stronger OATP2B1 inhibition compared with BCRP inhibition. The present study indicates that the "net-effect" of BCRP and OATP2B1 lead to a "positive" DDI, whereas a "negative" DDI (AUC ratio <0.8) is possible for "OATP2B1-alone" inhibitors. SIGNIFICANCE STATEMENT: Gut organic anion transporting polypeptide (OATP)2B1 and breast cancer resistance protein (BCRP) play key roles in rosuvastatin oral absorption and may determine its drug-drug interactions (DDIs). Based on a comprehensive dataset, it was found that rosuvastatin area under the curve ratios correlate significantly with BCRP inhibition, but not with OATP2B1 inhibition. Strong BCRP inhibition, with a G-value >100, translated to "positive" DDIs, whereas "OATP2B1-alone" inhibitors may lead to "negative" DDIs. For example, ronacaleret and elagolix significantly reduced rosuvastatin area under the curve due to strong OATP2B1 inhibition but weak BCRP inhibition.