Glucuronidation by UGT1A1 Is the Dominant Pathway of the Metabolic Disposition of Belinostat in Liver Cancer Patients

10.1371/journal.pone.0054522PLoS ONE81

Glucuronidation by UGT1A1 Is the Dominant Pathway of the Metabolic Disposition of Belinostat in Liver Cancer Patients

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.ClinicalTrials.gov NCT00321594</p

Association between glucuronidation of belinostat and UGT1A1 substrates (A, B, and C).

<p>A: Bilirubin-G; B: thyroxine-4-G/CPT-11; C: SN38-G/CPT11.</p

UGT1A1 expression on belinostat glucuronidation and impact of the common UGT1A1*28 promoter polymorphism.

<p>A: Correlation of belinostat glucuronide formation with UGT1A1 expression in human liver microsomes; B: Belinostat glucuronide formation by human liver microsomes according to wild-type, heterozygous and homozygous UGT1A1*28 genotypes.</p