Inhibition of Intestinal OATP2B1 by the Calcium Receptor Antagonist Ronacaleret Results in a Significant Drug-Drug Interaction by Causing a 2-Fold Decrease in Exposure of Rosuvastatin

Abstract

Rosuvastatin is a widely prescribed antihyperlipidemic which undergoes limited metabolism, but is an in vitro substrate of multiple transporters [organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP1A2, OATP2B1, sodium-taurocholate cotransporting polypeptide, breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), MRP4, organic anion transporter 3]. It is therefore frequently used as a probe substrate in clinical drug-drug interaction (DDI) studies to investigate transporter inhibition. Although each of these transporters is believed to play a role in rosuvastatin disposition, multiple pharmacogenetic studies confirm that OATP1B1 and BCRP play an important role in vivo. Ronacaleret, a drug-development candidate for treatment of osteoporosis (now terminated), was shown to inhibit OATP1B1 in vitro (IC = 11 µM), whereas it did not inhibit BCRP. Since a DDI risk through inhibition of OATP1B1 could not be discharged, a clinical DDI study was performed with rosuvastatin before initiation of phase II trials. Unexpectedly, coadministration with ronacaleret decreased rosuvastatin exposure by approximately 50%, whereas time of maximal plasma concentration and terminal half-life remained unchanged, suggesting decreased absorption and/or enhanced first-pass elimination of rosuvastatin. Of the potential in vivo rosuvastatin transporter pathways, two might explain the observed results: intestinal OATP2B1 and hepatic MRP4. Further investigations revealed that ronacaleret inhibited OATP2B1 (in vitro IC = 12 µM), indicating a DDI risk through inhibition of absorption. Ronacaleret did not inhibit MRP4, discharging the possibility of enhanced first-pass elimination of rosuvastatin (reduced basolateral secretion from hepatocytes into blood). Therefore, a likely mechanism of the observed DDI is inhibition of intestinal OATP2B1, demonstrating the in vivo importance of this transporter in rosuvastatin absorption in humans.

Proteomics‐Informed Prediction of Rosuvastatin Plasma Profiles in Patients With a Wide Range of Body Weight

“…For instance, the hydrophilic nature of rosuvastatin requires active uptake transport into the intestinal lumen and is determined by the apically located uptake transporter OATP2B1 and efflux transporter BCRP. 22,50 Interindividual variability of these intestinal proteins could affect the rosuvastatin PKs, and models incorporating intestinal absorption and distribution could shed light on these issues. 22,23 Furthermore, the effect of interindividual differences in hepatic biliary efflux of rosuvastatin, such as transport by BCRP (that was kept constant in this model) could also be of importance.…”

Intestinal Drug Interactions Mediated by OATPs: A Systematic Review of Preclinical and Clinical Findings

“…Not surprisingly, 7 of the clinical inhibitors that caused significant intestinal DDIs (apple juice, ergoloid mesylates, grapefruit juice, naringin, orange juice, quercetin, and ronacaleret) were found to inhibit OATP2B1 in vitro, and 5 (grapefruit juice, green tea, naringin, quercetin, and ronacaleret) were found to inhibit OATP1A2 in vitro. Ronacaleret inhibited OATP2B1 with an IC 50 value of 12 mM in transfected-HEK293 cells, 77 which is slightly over the threshold and, therefore, not presented in Supplementary Table 1. Similarly, quercetin was not included in Supplementary Table 2 because its inhibition parameters were over the threshold, with an IC 50 value of approximately 13.5 mM (substrate: atorvastatin or fexofenadine) and a K i value of 22 mM (substrate: bromosulfophthalein).…”

Transporters in Drug Development: 2018 ITC Recommendations for Transporters of Emerging Clinical Importance

“…Inhibition of intestinal OATP2B1 can decrease systemic exposure of OATP2B1 substrate drugs without increasing the terminal half‐life. Recent studies showed that ronacaleret, an inhibitor of OATP2B1, decreased rosuvastain plasma exposure by 50% without altering its terminal half‐life …”