Journal article
Role of the UGT2B17 deletion in exemestane pharmacogenetics
The pharmacogenomics journal, Vol.18(2), pp.295-300
04/2018
Handle:
https://hdl.handle.net/2376/104743
PMCID: PMC5700874
PMID: 28534527
Abstract
Exemestane (EXE) is an aromatase inhibitor used for the prevention and treatment of breast cancer. The major metabolic pathway for EXE is reduction to form the active 17β-dihydro-EXE (17β-DHE) and subsequent glucuronidation to 17β-hydroxy-EXE-17-O-β-D-glucuronide (17β-DHE-Gluc) by UGT2B17. The aim of the present study was to determine the effects of
UGT2B17
copy number variation on the levels of urinary and plasma 17β-DHE-Gluc and 17β-DHE in patients taking EXE. Ninety-six post-menopausal Caucasian breast cancer patients with ER+ breast tumors taking 25 mg EXE daily were recruited into this study.
UGT2B17
copy number was determined by a real-time PCR copy number variant assay and the levels of EXE, 17β-DHE and 17β-DHE-Gluc were quantified by UPLC/MS in patients’ urine and plasma. A 39-fold decrease (
P
<0.0001) in the levels of creatinine-adjusted urinary 17β-DHE-Gluc was observed among
UGT2B17
(*2/*2) subjects vs. subjects with the
UGT2B17
(*1/*1) genotype. The plasma levels of 17β-DHE-Gluc was decreased 29-fold (
P
<0.0001) in subjects with the
UGT2B17
(*2/*2) genotype vs. subjects with
UGT2B17
(*1/*1) genotype. The levels of plasma EXE-adjusted 17β-DHE was 28% higher (
P
=0.04) in subjects with the
UGT2B17
(*2/*2) genotype vs. subjects with the
UGT2B17
(*1/*1) genotype. These data indicate that UGT2B17 is the major enzyme responsible for 17β-DHE-Gluc formation
in vivo
and that the
UGT2B17
copy number variant may play a role in inter-individual variability in 17β-DHE levels
in vivo.
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Details
- Title
- Role of the UGT2B17 deletion in exemestane pharmacogenetics
- Creators
- Shaman LuoGang ChenCristina TruicaCynthia C BairdKim LeitzelPhilip Lazarus
- Publication Details
- The pharmacogenomics journal, Vol.18(2), pp.295-300
- Academic Unit
- Pharmaceutical Sciences, Department of
- Identifiers
- 99900546651301842
- Language
- English
- Resource Type
- Journal article