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

• DOI: 10.1124/dmd.116.072397
• Publication Date: 2016-10-14T02:23:28Z
• Authors: Marta Johnson; Dipal Patel; Christopher Matheny; May Ho; Liangfu Chen; Harma Ellens
• Keywords: Organic anion-transporting polypeptide; Abcg2

Rosuvastatin is a widely prescribed antihyperlipidemic which undergoes limited metabolism, but 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 2 (MRP2), MRP4, organic transporter 3]. It therefore frequently used as probe clinical drug-drug interaction (DDI) studies to investigate inhibition. Although each these believed play role rosuvastatin disposition, pharmacogenetic confirm that OATP1B1 and BCRP important vivo. Ronacaleret, drug-development candidate for treatment osteoporosis (now terminated), was shown inhibit (IC50 = 11 µM), whereas it did not BCRP. Since DDI risk through inhibition could be discharged, study performed with before initiation phase II trials. Unexpectedly, coadministration ronacaleret decreased exposure by approximately 50%, time maximal plasma concentration terminal half-life remained unchanged, suggesting absorption and/or enhanced first-pass elimination rosuvastatin. Of the potential vivo pathways, two might explain observed results: intestinal OATP2B1 hepatic MRP4. Further investigations revealed inhibited (in IC50 12 indicating absorption. Ronacaleret discharging possibility (reduced basolateral secretion from hepatocytes into blood). Therefore, likely mechanism demonstrating importance this humans.