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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 01; 45(1):27-34.DM

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+Show Affiliations

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.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.).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.).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.).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.).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.).

Pub Type(s)

Clinical Study
Journal Article

Language

eng

PubMed ID

27737931

Citation

Johnson, Marta, et al. "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 Metabolism and Disposition: the Biological Fate of Chemicals, vol. 45, no. 1, 2017, pp. 27-34.
Johnson M, Patel D, Matheny C, et al. 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;45(1):27-34.
Johnson, M., Patel, D., Matheny, C., Ho, M., Chen, L., & Ellens, H. (2017). 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 Metabolism and Disposition: the Biological Fate of Chemicals, 45(1), 27-34.
Johnson M, et al. 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;45(1):27-34. PubMed PMID: 27737931.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Johnson,Marta, AU - Patel,Dipal, AU - Matheny,Christopher, AU - Ho,May, AU - Chen,Liangfu, AU - Ellens,Harma, Y1 - 2016/10/13/ PY - 2016/07/25/received PY - 2016/10/12/accepted PY - 2016/10/16/pubmed PY - 2018/2/22/medline PY - 2016/10/15/entrez SP - 27 EP - 34 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 45 IS - 1 N2 - 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. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/27737931/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_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=27737931 DB - PRIME DP - Unbound Medicine ER -