Impact of UGT2B17 Gene Deletion on the Pharmacokinetics of 17-Hydroexemestane in Healthy Volunteers

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 micr...

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Bibliographic Details
Published in:Journal of clinical pharmacology 2016-07, Vol.56 (7), p.875-884
Main Authors: Chen, Shanly M., Atchley, Daniel H., Murphy, Michael A., Gurley, Bill J., Kamdem, Landry K.
Format: Article
Language:English
Subjects:
17-hydroexemestane
Androstadienes - metabolism
Androstadienes - pharmacokinetics
Aromatase Inhibitors - metabolism
Aromatase Inhibitors - pharmacokinetics
breast cancer
Estrogens
exemestane
Female
Gene Deletion
Glucuronosyltransferase - deficiency
Glucuronosyltransferase - genetics
Healthy Volunteers
Humans
Middle Aged
Minor Histocompatibility Antigens - genetics
pharmacokinetics and pharmacogenetics
Pilot Projects
UGT2B17 gene deletion
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Summary: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.
ISSN:0091-2700
1552-4604
DOI:10.1002/jcph.673