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Drug Metab Dispos. 2011 Sep;39(9):1747-54. doi: 10.1124/dmd.111.040188. Epub 2011 Jun 6.

Investigations of hydrazine cleavage of eltrombopag in humans.

Author information

1
Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 709 Swedeland Rd., King of Prussia, PA 19406, USA. yanli_2_deng@gsk.com

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.

PMID:
21646438
DOI:
10.1124/dmd.111.040188
[Indexed for MEDLINE]
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