title: 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 (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.
authors.affiliation: 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.
authors.forename: Marta
authors.initials: M
authors.lastname: Johnson
authors.affiliation: 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.).
authors.forename: Dipal
authors.initials: D
authors.lastname: Patel
authors.affiliation: 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.).
authors.forename: Christopher
authors.initials: C
authors.lastname: Matheny
authors.affiliation: 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.).
authors.forename: May
authors.initials: M
authors.lastname: Ho
authors.affiliation: 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.).
authors.forename: Liangfu
authors.initials: L
authors.lastname: Chen
authors.affiliation: 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.).
authors.forename: Harma
authors.initials: H
authors.lastname: Ellens
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000924:Anticholesteremic Agents / Q000097:blood / Q000493:pharmacokinetics*; D016466:CHO Cells; D003412:Cricetulus; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D057809:HEK293 Cells; D064368:Healthy Volunteers; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors*; D010666:Phenylpropionates / Q000494:pharmacology*; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*; D000068718:Rosuvastatin Calcium / Q000097:blood / Q000493:pharmacokinetics*; D013379:Substrate Specificity
chemical_list: D000924:Anticholesteremic Agents; D007189:Indans; D027361:Organic Anion Transporters; D010666:Phenylpropionates; D044169:Receptors, Calcium-Sensing; C450859:SLCO2B1 protein, human; D000068718:Rosuvastatin Calcium; C561716:ronacaleret