1. Academic Validation
  2. 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

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

  • Drug Metab Dispos. 2017 Jan;45(1):27-34. doi: 10.1124/dmd.116.072397.
Marta Johnson 1 Dipal Patel 2 Christopher Matheny 2 May Ho 2 Liangfu Chen 2 Harma Ellens 2
Affiliations

Affiliations

  • 1 Drug Metabolism and Pharmacokinetics (M.J., D.P., M.H., L.C., H.E.), and Translational Medicine (C.M.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pennington, New Jersey (D.P.) marta.2.johnson@gsk.com.
  • 2 Drug Metabolism and Pharmacokinetics (M.J., D.P., M.H., L.C., H.E.), and Translational Medicine (C.M.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pennington, New Jersey (D.P.).
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 (IC50 = 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 IC50 = 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.

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