title: Metabolism and disposition of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, in healthy human subjects.
abstract: 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 solution dose of [(14)C]eltrombopag (75 mg, 100 μCi). Eltrombopag was well tolerated. The drug was quickly absorbed and was the predominant circulating component in plasma (accounting for 63% of the total plasma radioactivity). A mono-oxygenation metabolite (M1) and acyl glucuronides (M2) of eltrombopag were minor circulating components. The predominant route of elimination of radioactivity was fecal (58.9%). Feces contained approximately 20% of dose as glutathione-related conjugates (M5, M6, and M7) and another 20% as unchanged eltrombopag. The glutathione conjugates were probably detoxification products of a p-imine methide intermediate formed by metabolism of M1, which arises through cytochrome P450-dependent processes. Low levels of covalently bound drug-related intermediates to plasma proteins, which could result from the reaction of the imine methide or acyl glucuronide conjugates with proteins, were detected. The bound material contributes to the longer plasma elimination half-life of radioactivity. Renal elimination of conjugates of hydrazine cleavage metabolites (mostly as M3 and M4) accounted for 31% of the radiodose, with no unchanged eltrombopag detected in urine.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 709 Swedeland Rd., King of Prussia, PA 19406, USA. yanli_2_deng@gsk.com
authors.forename: Yanli
authors.initials: Y
authors.lastname: Deng
authors.forename: Armina
authors.initials: A
authors.lastname: Madatian
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Wire
authors.forename: Carolyn
authors.initials: C
authors.lastname: Bowen
authors.forename: Jung Wook
authors.initials: JW
authors.lastname: Park
authors.forename: Daphne
authors.initials: D
authors.lastname: Williams
authors.forename: Bin
authors.initials: B
authors.lastname: Peng
authors.forename: Ernest
authors.initials: E
authors.lastname: Schubert
authors.forename: Frances
authors.initials: F
authors.lastname: Gorycki
authors.forename: Mark
authors.initials: M
authors.lastname: Levy
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gorycki
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001565:Benzoates / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000097:blood; D005978:Glutathione / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D006834:Hydrazines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D011720:Pyrazoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D053628:Receptors, Thrombopoietin / Q000819:agonists* / Q000378:metabolism
chemical_list: D001565:Benzoates; D001798:Blood Proteins; D020719:Glucuronides; D006834:Hydrazines; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; C029424:hydrazine; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; C520809:eltrombopag