Glucuronidation by UGT1A1 is the dominant pathway of the metabolic disposition of belinostat in liver cancer patients

PLoS One. 2013;8(1):e54522. doi: 10.1371/journal.pone.0054522. Epub 2013 Jan 30.

Abstract

Belinostat is a hydroxamate class HDAC inhibitor that has demonstrated activity in peripheral T-cell lymphoma and is undergoing clinical trials for non-hematologic malignancies. We studied the pharmacokinetics of belinostat in hepatocellular carcinoma patients to determine the main pathway of metabolism of belinostat. The pharmacokinetics of belinostat in liver cancer patients were characterized by rapid plasma clearance of belinostat with extensive metabolism with more than 4-fold greater relative systemic exposure of major metabolite, belinostat glucuronide than that of belinostat. There was significant interindividual variability of belinostat glucuronidation. The major pathway of metabolism involves UGT1A1-mediated glucuronidation and a good correlation has been identified between belinostat glucuronide formation and glucuronidation of known UGT1A1 substrates. In addition, liver microsomes harboring UGT1A1*28 alleles have lower glucuronidation activity for belinostat compared to those with wildtype UGT1A1. The main metabolic pathway of belinostat is through glucuronidation mediated primarily by UGT1A1, a highly polymorphic enzyme. The clinical significance of this finding remains to be determined.

Trial registration: ClinicalTrials.gov NCT00321594.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / toxicity
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Drug Stability
  • Gene Expression
  • Genotype
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism*
  • Histone Deacetylase Inhibitors / metabolism
  • Histone Deacetylase Inhibitors / pharmacokinetics*
  • Histone Deacetylase Inhibitors / toxicity
  • Humans
  • Hydrogen-Ion Concentration
  • Hydroxamic Acids / metabolism
  • Hydroxamic Acids / pharmacokinetics*
  • Hydroxamic Acids / toxicity
  • Kinetics
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Metabolic Networks and Pathways*
  • Metabolome
  • Microsomes, Liver / metabolism
  • Substrate Specificity
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacokinetics*
  • Sulfonamides / toxicity

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Sulfonamides
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • belinostat

Associated data

  • ClinicalTrials.gov/NCT00321594

Grants and funding

The study was sponsored by the National Research Foundation of Singapore (Experimental Therapeutics Program) and the National Medical Research Council of Singapore (NMRC/CSA/021/2010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.