Metabolism and Disposition of Eltrombopag, an Oral, Nonpeptide Thrombopoietin Receptor Agonist, in Healthy Human Subjects
Open Access
- 6 June 2011
- journal article
- clinical trial
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Drug Metabolism and Disposition
- Vol. 39 (9), 1734-1746
- https://doi.org/10.1124/dmd.111.040170
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 [14C]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.Keywords
This publication has 20 references indexed in Scilit:
- Investigations of Hydrazine Cleavage of Eltrombopag in HumansDrug Metabolism and Disposition, 2011
- Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trialThe Lancet, 2009
- A Novel Bioactivation Pathway for 2-[2-(2,6-Dichlorophenyl)aminophenyl]ethanoic Acid (Diclofenac) Initiated by Cytochrome P450-Mediated Oxidative DecarboxylationDrug Metabolism and Disposition, 2008
- Eltrombopag for the Treatment of Chronic Idiopathic Thrombocytopenic PurpuraThe New England Journal of Medicine, 2007
- Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis CThe New England Journal of Medicine, 2007
- Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonistBlood, 2007
- THE ROLE OF METABOLIC ACTIVATION IN DRUG-INDUCED HEPATOTOXICITYAnnual Review of Pharmacology and Toxicology, 2005
- Drug−Protein Adducts: An Industry Perspective on Minimizing the Potential for Drug Bioactivation in Drug Discovery and DevelopmentChemical Research in Toxicology, 2003
- Studies on the Metabolism of Troglitazone to Reactive Intermediates in Vitro and in Vivo. Evidence for Novel Biotransformation Pathways Involving Quinone Methide Formation and Thiazolidinedione Ring ScissionChemical Research in Toxicology, 2000
- Formation and reactivity of alternative quinone methides from butylated hydroxytoluene: possible explanation for species-specific pneumotoxicityChemical Research in Toxicology, 1990