Investigations of Hydrazine Cleavage of Eltrombopag in Humans

Abstract

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.

Metabolism and Disposition of Eltrombopag, an Oral, Nonpeptide Thrombopoietin Receptor Agonist, in Healthy Human Subjects

“…The cleavage products are then quickly absorbed, metabolized, and eliminated in urine. As demonstrated in mice with one in vitro cleavage product of eltrombopag, SB-611855, the plasma concentrations of this cleavage product reached a maximum within 5 min after oral administration of SB-611855 but decreased below the limit of quantitation within 3 h postdose (Deng et al, 2011). This rapid rate of elimination might explain the absence of cleavage products in circulation in metabolism studies in which metabolite sampling typically started from 4 h postdose.…”

“…The urinary metabolites (cleavage products of eltrombopag) were not observed in human plasma. Eltrombopag is cleaved by gut microbes (Deng et al, 2011). The cleavage products are then quickly absorbed, metabolized, and eliminated in urine.…”

Gut microbiome interactions with drug metabolism, efficacy, and toxicity

“…Hydrazone linkages in drugs are also susceptible to reductive cleavage by the gut microbiota as evidenced by studies in dogs35 and humans36 on the drug levosimendan, and in humans in the case of eltrombopag37. Reductive metabolism also occurs for sulphur-containing compounds as seen in the microbiota-driven reduction of the sulphoxide-containing drugs sulphinpyrazone and sulindac38 via the formation of sulphides on incubation with faeces (human or rabbit).…”

Dissecting the human gut microbiome to better decipher drug liability: A once-forgotten organ takes center stage

“… Pseudomonas spp. Enterococci [45] , [59] Alkene reduction Digoxin Eggerthella lenta [61] Ketone reduction Tacrolimus (+nabumetone, pyrazinone, darolutamide) Faecalibacterium prausnitzii [20] Hydrazine, hydrazone cleavage Levosimendan Eltrombopag [49] , [182] Reductive Imidazole ring cleavage Metronidazole Clostridium perfringens [183] Potassium oxonate reduction Potassium oxonate [184] Dehydroxylation Dopamine (+fostamatinib) Eggerthella lenta [148] , [185] Reductive isoxazole ring cleavage Zonisamide (+risperidone) Clostridium sporogenes [186] , [187] Hydrolysis Amide hydrolysis (and proteolysis) Azetirelin (+calcitonin, insulin) [15] , [188] Glucuronide hydrolysis Irinotecan metabolite SN-38 glucuronide Sorivudine (+diclofenac glucuronide, indomethacin glucuronide, ketoprofen glucuronide, hesperidin) Bacteroides B. vulgatus, B. thetaiotaomicron, B. fragilis, B. uniformis, B. eggerthii Escherichia coli [17] , ...…”