PT  - JOURNAL ARTICLE
AU  - Yanli Deng
AU  - Martin Rogers
AU  - Caroline Sychterz
AU  - Kimberly Talley
AU  - Yanwen Qian
AU  - David Bershas
AU  - May Ho
AU  - Wei Shi
AU  - Emile P. Chen
AU  - Cosette Serabjit-Singh
AU  - Peter D. Gorycki
TI  - Investigations of Hydrazine Cleavage of Eltrombopag in Humans
AID  - 10.1124/dmd.111.040188
DP  - 2011 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 1747--1754
VI  - 39
IP  - 9
4099  - http://dmd.aspetjournals.org/content/39/9/1747.short
4100  - http://dmd.aspetjournals.org/content/39/9/1747.full
SO  - Drug Metab Dispos2011 Sep 01; 39
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.