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A pharmacogenetic study of vorinostat glucuronidation
Soonmo Peter Kang1, Jacqueline Ramirez, Larry House
1Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Pharmacogenetics and Genomics
|August 24, 2010
Summary
Genetic variants in uridine 5'-diphosphate-glucuronosyltransferases (UGTs) may explain vorinostat pharmacokinetic variability. UGT2B17 plays a key role in vorinostat metabolism, and its deletion may affect drug clearance.
Area of Science:
- Pharmacology
- Genetics
- Drug Metabolism
Background:
- Vorinostat (suberoylanilide hydroxamic acid) is an oral histone deacetylase inhibitor.
- Phase 1 studies revealed significant interindividual pharmacokinetic variability for vorinostat.
Purpose of the Study:
- To investigate the role of uridine 5'-diphosphate-glucuronosyltransferases (UGTs) genetic variants in vorinostat pharmacokinetic variability.
- To identify specific UGT enzymes involved in vorinostat metabolism.
Main Methods:
- Screening of baculosomes expressing human UGTs and human liver microsomes for vorinostat glucuronidation activity.
- Comparison of enzymatic activity between liver microsomes with and without the UGT2B17 gene.
Main Results:
- UGT2B17 exhibited the highest vorinostat glucuronidation activity.
- Liver microsomes with at least one copy of UGT2B17 demonstrated significantly greater activity compared to those with a null genotype (P<0.004).
Conclusions:
- UGT2B17 is crucial for the hepatic glucuronidation of vorinostat.
- The UGT2B17 gene deletion polymorphism may influence vorinostat biotransformation and clearance.
- The clinical significance of the UGT2B17 genetic variant on vorinostat metabolism and efficacy requires further investigation.
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