title: Pharmacokinetics and hepatic uptake of eltrombopag, a novel platelet-increasing agent.
abstract: Eltrombopag (ELT) is a novel thrombopoietin receptor agonist for the treatment of idiopathic thrombocytopenic purpura. Previous reports indicate that ELT is mainly eliminated in the liver, although its pharmacokinetic profile has not yet been clarified in detail. The purpose of the present study is to investigate the overall elimination mechanism of ELT. After intravenous administration of ELT to rats, approximately 40% of unchanged ELT was excreted into the bile in 72 h, whereas less than 0.02% of the dose was excreted in urine, indicating that liver is the major elimination organ for ELT. The total clearance was much lower than the hepatic blood flow rate and comparable with hepatic uptake clearance obtained from integration plot analysis. Coadministration of rifampicin, an organic anion transporter inhibitor, reduced both total clearance and hepatic uptake clearance of ELT. These results suggest that hepatic uptake is the rate-limiting process in the overall elimination of ELT. To further characterize the uptake mechanism, uptake of ELT by freshly isolated mouse hepatocytes was examined. The ELT uptake showed concentration and energy dependence and was inhibited by various compounds, including not only organic anions but also organic cations. Hepatic uptake clearance in vivo was reduced by coadministration of an organic cation, tetrapentylammonium. Finally, uptake of ELT was observed in human embryonic kidney 293 cells transfected with human hepatic transporters organic anion-transporting polypeptide (OATP) 1B1 and OATP2B1 and organic cation transporter OCT1. These results suggest that multiple transporters, including organic anion transporters and organic cation transporters, are involved in hepatic ELT uptake.
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sugiura
authors.forename: Saki
authors.initials: S
authors.lastname: Umeda
authors.forename: Kazuki
authors.initials: K
authors.lastname: Matsubara
authors.forename: Masato
authors.initials: M
authors.lastname: Horikawa
authors.forename: Noritaka
authors.initials: N
authors.lastname: Nakamichi
authors.forename: David L
authors.initials: DL
authors.lastname: Silver
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ishiwata
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
mesh_terms: D000818:Animals; D001565:Benzoates / Q000097:blood / Q000493:pharmacokinetics*; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D027361:Organic Anion Transporters / Q000235:genetics / Q000502:physiology; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000502:physiology; D010976:Platelet Count; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000097:blood / Q000188:drug therapy; D011720:Pyrazoles / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D014018:Tissue Distribution
chemical_list: D001565:Benzoates; D006834:Hydrazines; D047908:Intracellular Signaling Peptides and Proteins; D027381:Liver-Specific Organic Anion Transporter 1; D008565:Membrane Proteins; D027361:Organic Anion Transporters; D027702:Organic Cation Transporter 1; C514896:PDZK1 protein, mouse; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; C503999:SLCO1B1 protein, human; C450859:SLCO2B1 protein, human; C520809:eltrombopag