Interaction of Novel Platelet-Increasing Agent Eltrombopag with Rosuvastatin via Breast Cancer Resistance Protein in Humans

@article{Takeuchi2014InteractionON,
  title={Interaction of Novel Platelet-Increasing Agent Eltrombopag with Rosuvastatin via Breast Cancer Resistance Protein in Humans},
  author={Kazuya Takeuchi and Tomoko Sugiura and Kazuki Matsubara and R. Sato and Takuya Shimizu and Yusuke Masuo and Masato Horikawa and Noritaka Nakamichi and Norihisa Ishiwata and Yukio Kato},
  journal={Drug Metabolism and Disposition},
  year={2014},
  volume={42},
  pages={726 - 734}
}
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… 
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Citation Type

Therapeutic Doses of Eltrombopag do not Inhibit Hepatic BCRP in Healthy Volunteers: Intravenous Ceftriaxone as a Model.
  • D. V. Neves, C. Vieira, A. Rocha, V. Lanchote
  • Biology, Medicine
    Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques
  • 2018
TLDR
The results do not support the existence of a clinical pharmacokinetic drug interaction involving hepatic BCRP in human subjects receiving intravenous ceftriaxone and oral eltrombopag.
Effect of Ursolic Acid on Breast Cancer Resistance Protein-mediated Transport of Rosuvastatin In Vivo and Vitro.
  • J. Wen, X. Wei, +4 authors Jian Zhou
  • Biology, Medicine
    Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih
  • 2015
Characterization of Long-Lasting Oatp Inhibition by Typical Inhibitor Cyclosporine A and In Vitro-In Vivo Discrepancy in Its Drug Interaction Potential in Rats.
Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs
TLDR
These endogenous substrates can complement existing OATP1B‐mediated drug–drug interaction risk assessment approaches based on agency guidelines in early clinical trials and are supported by the good correlation of AUC0‐24h between the endogenous compounds and the probe drugs.
Organic Cation Transporter 1 Is Responsible for Hepatocellular Uptake of the Tyrosine Kinase Inhibitor Pazopanib
TLDR
The present findings suggest that OCT1 is responsible for hepatic uptake of pazopanib, and has the potential for clinically relevant inhibition of human OCT1.
Febuxostat, But Not Allopurinol, Markedly Raises the Plasma Concentrations of the Breast Cancer Resistance Protein Substrate Rosuvastatin
TLDR
The results suggest that febuxostat increases rosuvastatin exposure by inhibiting its BCRP‐mediated efflux in the small intestine, and may serve as a useful index inhibitor of B CRP in drug‐drug interaction studies in humans.
ABCG2/BCRP: variants, transporter interaction profile of substrates and inhibitors
TLDR
The aims of the review are to cover transporter interaction profile of substrates and inhibitors that can be utilized to test interaction of drug candidates with ABCG2, to highlight main characteristics of in vitro testing and to describe the structural basis of the broad substrate specificity of the protein.
Telmisartan increases systemic exposure to rosuvastatin after single and multiple doses, and in vitro studies show telmisartan inhibits ABCG2-mediated transport of rosuvastatin
PurposeThe ATP-binding cassette transporter G2 (ABCG2) plays an important role in the disposition of rosuvastatin. Telmisartan, a selective angiotension-II type 1 (AT1) receptor blocker, inhibits the…
Drug–drug interactions that interfere with statin metabolism
TLDR
The pharmacokinetic aspects of the drug–drug interaction with statins and genetic polymorphisms in CYPs, which are involved in the metabolism of statins, are discussed and the importance of establishing a system utilizing electronic medical information practically to avoid adverse drug reactions is highlighted.
Comparing Various In Vitro Prediction Criteria to Assess the Potential of a New Molecular Entity to Inhibit Organic Anion Transporting Polypeptide 1B1
TLDR
Various prediction methods and cutoff criteria based on in vitro inhibition data to assess the potential of a new molecular entity to inhibit OATP1B1 in vivo were compared and it was reasonable to determine the need to perform clinical DDI studies with OatP1 B1 substrates with similar positive and negative predictive values.
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References

SHOWING 1-10 OF 37 REFERENCES
Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers.
TLDR
Concomitant administration of eltrombopag with rosuvastatin was associated with increased rosuVastatin exposure via inhibition of drug transporters, and the therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use ofEltrom bopag.
Preclinical Activity of Eltrombopag (SB-497115), an Oral, Nonpeptide Thrombopoietin Receptor Agonist
TLDR
In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production.
Pharmacokinetics and Hepatic Uptake of Eltrombopag, a Novel Platelet-Increasing Agent
TLDR
The results suggest that hepatic uptake is the rate-limiting process in the overall elimination of ELT, and multiple transporters, including organic aniontransporters and organic cation transporators, are involved in hepatic ELT uptake.
Metabolism and Disposition of Eltrombopag, an Oral, Nonpeptide Thrombopoietin Receptor Agonist, in Healthy Human Subjects
The metabolism and disposition of eltrombopag, the first-in-class small molecule human thrombopoietin receptor agonist, were studied in six healthy men after a single oral administration of a…
Assessment of the Pharmacokinetic Interaction between Eltrombopag and Lopinavir-Ritonavir in Healthy Adult Subjects
TLDR
It is suggested that platelet counts should be monitored and the eltrombopag dose adjusted accordingly if LPV/RTV therapy is initiated or discontinued and the potential drug-drug interaction between lopinavir (LPV)/RTV is evaluated.
Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist.
TLDR
In this phase 1 placebo-controlled clinical trial in 73 healthy male subjects, eltrombopag was administered as once-daily oral capsules for 10 days at doses of 5, 10, 25, 30, 50, and 75 mg, and there were no apparent differences in the incidence or severity of adverse events in subjects receiving active or placebo study medication.
Biological Activity and Selectivity for Tpo Receptor of the Orally Bioavailable, Small Molecule Tpo Receptor Agonist, SB-497115.
TLDR
SB-497115 is the first non-peptide small molecule TpoR agonist to demonstrate activity in human in vitro bone marrow assays and demonstrate pharmacological activity in humans.
Effect of Hepatic or Renal Impairment on Eltrombopag Pharmacokinetics
TLDR
Results suggest that patients with renal impairment may initiate eltrombopag with the standard 50‐mg once‐daily starting regimen, whereas patients with moderate or severe hepatic impairment should consider a lower 25‐mgonce‐daily regimen.
Involvement of Multiple Transporters in the Hepatobiliary Transport of Rosuvastatin
Rosuvastatin is an HMG-CoA reductase inhibitor and one of the most hydrophilic among the commercially available statins. It is efficiently accumulated in the liver and excreted into the bile in an…
Physiologically Based Pharmacokinetic Modeling to Predict Transporter-Mediated Clearance and Distribution of Pravastatin in Humans
TLDR
The model allows the prediction of the disposition of pravastatin in humans and suggests that changes in the OATP1B1 activities may have a small and a large impact on the therapeutic efficacy and side effect (myopathy) of pavastatin, respectively, whereas those in the MRP2 activities might have opposite impacts.
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