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Impact of UGT2B17 Gene Deletion on the Pharmacokinetics of 17‐Hydroexemestane in Healthy Volunteers
Author(s) -
Chen Shanly M.,
Atchley Daniel H.,
Murphy Michael A.,
Gurley Bill J.,
Kamdem Landry K.
Publication year - 2016
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.673
Subject(s) - exemestane , pharmacokinetics , glucuronidation , pharmacology , genotype , medicine , aromatase inhibitor , aromatase , pharmacogenetics , metabolite , allele , gene , biology , cancer , breast cancer , microsome , in vitro , genetics
Exemestane is an aromatase inhibitor drug used for the treatment of hormone‐dependent breast cancer. 17‐Hydroexemestane, the major and biologically active metabolite of exemestane in humans, is eliminated via glucuronidation by the polymorphic UGT2B17 phase II drug‐metabolizing enzyme. Previous microsomal studies have shown that UGT2B17 gene deletion affects the intrinsic hepatic clearances of 17‐hydroexemestane in vitro. In this open‐label study we set out to assess the effect of UGT2B17 gene deletion on the pharmacokinetics of 17‐hydroexemestane in healthy female volunteers with and without UGT2B17 . To achieve this goal, 14 healthy postmenopausal women (8 carriers of the homozygous UGT2B17 wild‐type allele and 6 carriers of the homozygous UGT2B17 gene‐deletion allele) were enrolled and invited to receive a single 25‐mg oral dose of exemestane. Pharmacokinetics was assessed over 72 hours postdosing. Our results showed that there were statistically significant differences in plasma 17‐hydroexemestane AUC 0‐∞ ( P = .0007) and urine 17‐hydroexemestane C 24h ( P = .001) between UGT2B17 genotype groups. Our data suggest that UGT2B17 gene deletion influences 17‐hydroexemestane pharmacokinetics in humans.