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Interaction of novel platelet-increasing agent eltrombopag with rosuvastatin via breast cancer resistance protein in humans.
Drug Metab Dispos. 2014 Apr; 42(4):726-34.DM

Abstract

Eltrombopag (ELT), an orally available thrombopoietin receptor agonist, is a substrate of organic anion transporting polypeptide 1B1 (OATP1B1), and coadministration of ELT increases the plasma concentration of rosuvastatin in humans. Since the pharmacokinetic mechanism(s) of the interaction is unknown, the present study aimed to clarify the drug interaction potential of ELT at transporters. The OATP1B1-mediated uptake of ELT was inhibited by several therapeutic agents used to treat lifestyle diseases. Among them, rosuvastatin was a potent inhibitor with an IC(50) of 0.05 µM, which corresponds to one-seventh of the calculated maximum unbound rosuvastatin concentration at the inlet to the liver. Nevertheless, a simulation study using a physiologically based pharmacokinetic model predicted that the effect of rosuvastatin on the pharmacokinetic profile of ELT in vivo would be minimal. On the other hand, ELT potently inhibited uptake of rosuvastatin by OATP1B1 and human hepatocytes, with an IC(50) of 0.1 µM. However, the results of the simulation study indicated that inhibition of OATP1B1 by ELT can only partially explain the clinically observed interaction with rosuvastatin. ELT also inhibited transcellular transport of rosuvastatin in MDCKII cells stably expressing breast cancer resistance protein (BCRP), and was found to be a substrate of BCRP. The interaction of ELT with rosuvastatin can be almost quantitatively explained on the assumption that intestinal secretion of rosuvastatin is essentially completely inhibited by ELT. These results suggest that BCRP in small intestine may be the major target for interaction between ELT and rosuvastatin in humans.

Authors+Show Affiliations

Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan (K.T., T.S., K.M., R.S., T.S., Y.M., N.N., Y.K.); and Pharmaceutical Research Department, Biological Research Laboratories, Nissan Chemical Industries, Ltd., Saitama, Japan (K.T., M.H., N.I.).No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24440960

Citation

Takeuchi, Kazuya, et al. "Interaction of Novel Platelet-increasing Agent Eltrombopag With Rosuvastatin Via Breast Cancer Resistance Protein in Humans." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 42, no. 4, 2014, pp. 726-34.
Takeuchi K, Sugiura T, Matsubara K, et al. Interaction of novel platelet-increasing agent eltrombopag with rosuvastatin via breast cancer resistance protein in humans. Drug Metab Dispos. 2014;42(4):726-34.
Takeuchi, K., Sugiura, T., Matsubara, K., Sato, R., Shimizu, T., Masuo, Y., Horikawa, M., Nakamichi, N., Ishiwata, N., & Kato, Y. (2014). Interaction of novel platelet-increasing agent eltrombopag with rosuvastatin via breast cancer resistance protein in humans. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 42(4), 726-34. https://doi.org/10.1124/dmd.113.054767
Takeuchi K, et al. Interaction of Novel Platelet-increasing Agent Eltrombopag With Rosuvastatin Via Breast Cancer Resistance Protein in Humans. Drug Metab Dispos. 2014;42(4):726-34. PubMed PMID: 24440960.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interaction of novel platelet-increasing agent eltrombopag with rosuvastatin via breast cancer resistance protein in humans. AU - Takeuchi,Kazuya, AU - Sugiura,Tomoko, AU - Matsubara,Kazuki, AU - Sato,Ren, AU - Shimizu,Takuya, AU - Masuo,Yusuke, AU - Horikawa,Masato, AU - Nakamichi,Noritaka, AU - Ishiwata,Norihisa, AU - Kato,Yukio, Y1 - 2014/01/17/ PY - 2014/1/21/entrez PY - 2014/1/21/pubmed PY - 2014/10/29/medline SP - 726 EP - 34 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 42 IS - 4 N2 - Eltrombopag (ELT), an orally available thrombopoietin receptor agonist, is a substrate of organic anion transporting polypeptide 1B1 (OATP1B1), and coadministration of ELT increases the plasma concentration of rosuvastatin in humans. Since the pharmacokinetic mechanism(s) of the interaction is unknown, the present study aimed to clarify the drug interaction potential of ELT at transporters. The OATP1B1-mediated uptake of ELT was inhibited by several therapeutic agents used to treat lifestyle diseases. Among them, rosuvastatin was a potent inhibitor with an IC(50) of 0.05 µM, which corresponds to one-seventh of the calculated maximum unbound rosuvastatin concentration at the inlet to the liver. Nevertheless, a simulation study using a physiologically based pharmacokinetic model predicted that the effect of rosuvastatin on the pharmacokinetic profile of ELT in vivo would be minimal. On the other hand, ELT potently inhibited uptake of rosuvastatin by OATP1B1 and human hepatocytes, with an IC(50) of 0.1 µM. However, the results of the simulation study indicated that inhibition of OATP1B1 by ELT can only partially explain the clinically observed interaction with rosuvastatin. ELT also inhibited transcellular transport of rosuvastatin in MDCKII cells stably expressing breast cancer resistance protein (BCRP), and was found to be a substrate of BCRP. The interaction of ELT with rosuvastatin can be almost quantitatively explained on the assumption that intestinal secretion of rosuvastatin is essentially completely inhibited by ELT. These results suggest that BCRP in small intestine may be the major target for interaction between ELT and rosuvastatin in humans. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/24440960/Interaction_of_novel_platelet_increasing_agent_eltrombopag_with_rosuvastatin_via_breast_cancer_resistance_protein_in_humans_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=24440960 DB - PRIME DP - Unbound Medicine ER -