RT Journal Article SR Electronic T1 Investigations of Hydrazine Cleavage of Eltrombopag in Humans JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1747 OP 1754 DO 10.1124/dmd.111.040188 VO 39 IS 9 A1 Yanli Deng A1 Martin Rogers A1 Caroline Sychterz A1 Kimberly Talley A1 Yanwen Qian A1 David Bershas A1 May Ho A1 Wei Shi A1 Emile P. Chen A1 Cosette Serabjit-Singh A1 Peter D. Gorycki YR 2011 UL http://dmd.aspetjournals.org/content/39/9/1747.abstract AB 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.