title: Impact of UGT2B17 Gene Deletion on the Pharmacokinetics of 17-Hydroexemestane in Healthy Volunteers.
abstract: 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 AUC0-∞ (P = .0007) and urine 17-hydroexemestane C24h (P = .001) between UGT2B17 genotype groups. Our data suggest that UGT2B17 gene deletion influences 17-hydroexemestane pharmacokinetics in humans.
authors.affiliation: Harding University College of Pharmacy, Searcy, AR, USA.
authors.forename: Shanly M
authors.initials: SM
authors.lastname: Chen
authors.affiliation: University of Pikeville, Kentucky College of Osteopathic Medicine, Pikeville, KY, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Atchley
authors.affiliation: Harding University Physician Assistant Program, Searcy, AR, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Murphy
authors.affiliation: University of Arkansas for Medical Sciences, College of Pharmacy, Little Rock, AR, USA.
authors.forename: Bill J
authors.initials: BJ
authors.lastname: Gurley
authors.affiliation: Harding University College of Pharmacy, Searcy, AR, USA.
authors.forename: Landry K
authors.initials: LK
authors.lastname: Kamdem
mesh_terms: D000730:Androstadienes / Q000378:metabolism / Q000493:pharmacokinetics*; D047072:Aromatase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D017353:Gene Deletion; D014453:Glucuronosyltransferase / Q000172:deficiency* / Q000235:genetics*; D064368:Healthy Volunteers; D006801:Humans; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D010865:Pilot Projects
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; D015778:Minor Histocompatibility Antigens; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human; C056516:exemestane
keywords: 17-hydroexemestane; UGT2B17 gene deletion; breast cancer; exemestane; pharmacokinetics and pharmacogenetics