title: Investigations of hydrazine cleavage of eltrombopag in humans.
abstract: After oral administration to humans, eltrombopag undergoes extensive cleavage of its hydrazine linkage to metabolites, which are exclusively eliminated in urine. In vitro, the cleavage pathway was not detected in systems using cytochrome P450 enzymes, renal or hepatic microsomes, or hepatocytes but was readily evident after anaerobic incubation with rodent cecal contents or human fecal homogenate. Antibiotic treatment in vitro and in vivo inhibited eltrombopag cleavage, further indicating that cleavage is via gut microbes. Antibiotic treatment did not alter the systemic exposure of eltrombopag in mice. Oral and intravenous pharmacokinetic characterization in the mice with one of the cleavage products indicated that it was readily absorbed, conjugated, and eliminated in urine, consistent with its fate after oral administration of eltrombopag. Variation in this microbial pathway, for example by antibiotic cotherapy, is unlikely to be clinically significant.
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: Martin
authors.initials: M
authors.lastname: Rogers
authors.forename: Caroline
authors.initials: C
authors.lastname: Sychterz
authors.forename: Kimberly
authors.initials: K
authors.lastname: Talley
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Qian
authors.forename: David
authors.initials: D
authors.lastname: Bershas
authors.forename: May
authors.initials: M
authors.lastname: Ho
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Emile P
authors.initials: EP
authors.lastname: Chen
authors.forename: Cosette
authors.initials: C
authors.lastname: Serabjit-Singh
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gorycki
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001565:Benzoates / Q000378:metabolism* / Q000493:pharmacokinetics; D002432:Cecum / Q000187:drug effects / Q000382:microbiology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000378:metabolism* / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism* / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley
chemical_list: D000900:Anti-Bacterial Agents; D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; C029424:hydrazine; D003577:Cytochrome P-450 Enzyme System; C520809:eltrombopag