A pharmacogenetic study of vorinostat glucuronidation

Soonmo Peter Kang, Jacqueline Ramirez, Larry House, Wei Zhang, Snezana Mirkov, Wanqing Liu, Eden Haverfield, Mark J. Ratain

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

High interindividual pharmacokinetic variability was observed in phase 1 studies of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor. Thus, we hypothesized that the variability can be explained by genetic variants of the uridine 5′-diphosphate- glucuronosyltransferases (UGTs) involved in vorinostat metabolism. Baculosomes expressing human UGTs and 52 human liver microsomes were screened for vorinostat glucuronidation activity to identify the potential enzymes and functional variants. UGT2B17 had the largest activity. Human liver microsomes with at least one copy of UGT2B17 showed significantly greater enzymatic activity than those with UGT2B17 null genotype (P<0.004). UGT2B17 plays an important role in vorinostat hepatic glucuronidation and the gene deletion polymorphism may influence vorinostat biotransformation and clearance. The clinical impact of this UGT2B17 genetic variant on vorinostat metabolism and drug effect is unknown.

Original languageEnglish (US)
Pages (from-to)638-641
Number of pages4
JournalPharmacogenetics and genomics
Volume20
Issue number10
DOIs
StatePublished - Oct 2010

Keywords

  • pharmacogenetics
  • suberoylanilide hydroxamic acid
  • uridine diphosphate-glucuronosyltransferases

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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