A pharmacogenetic study of vorinostat glucuronidation.
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.
Kang
Soonmo Peter
SP
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
Ramirez
Jacqueline
J
House
Larry
L
Zhang
Wei
W
Mirkov
Snezana
S
Liu
Wanqing
W
Haverfield
Eden
E
Ratain
Mark J
MJ
D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005838:Genotype; D020719:Glucuronides / Q000235:genetics* / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism*; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010597:Pharmacogenetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012044:Regression Analysis; D013379:Substrate Specificity / Q000187:drug effects; D000077337:Vorinostat
D020719:Glucuronides; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D000077337:Vorinostat; D014453:Glucuronosyltransferase