Role of the UGT2B17 deletion in exemestane pharmacogenetics

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.

Identification and Quantification of Novel Major Metabolites of the Steroidal Aromatase Inhibitor, Exemestane

“…Therefore, these conjugates likely comprise an even larger proportion of EXE metabolites in the urine and plasma of women taking EXE, further increasing the importance of cysteine conjugate formation and decreasing the overall importance of glucuronidation in the metabolism of EXE. In addition, this further supports previous results demonstrating only small changes in plasma 17b-DHE and no change in urinary 17b-DHE in subjects deficient in DHE glucuronidation capacity since the glucuronide comprises a relatively low percentage of EXE metabolites in vivo (Luo et al, 2018).…”

“…in urinary or plasma EXE and 17b-DHE were observed in subjects taking EXE who were homozygous for the UGT2B17 deletion polymorphism (i.e., with no active UGT2B17) in previous studies (Luo et al, 2018).…”

“…Previous in vitro studies in a panel of human liver microsomes demonstrated that deletion of the UGT2B17 gene resulted in significant decreases in 17b-DHE-Gluc formation (Sun et al, 2010). Although drastic decreases in urinary and plasma 17b-DHE-Gluc levels were also associated with increasing numbers of the UGT2B17 deletion allele in women taking EXE (e.g., up to 29-fold in plasma), only a small (1.3-fold) corresponding increase in plasma 17b-DHE was observed in the same women (Luo et al, 2018). In the present study, 17b-DHE-Gluc was demonstrated to comprise 36% of the total quantified EXE metabolites in plasma, levels that were approximately equal to that observed for both of the cysteine conjugates combined (which comprised 35% of the total quantified plasma EXE metabolites) and only slightly more than that observed for 6-EXE-cys alone (which comprised 23% of total quantified plasma EXE metabolites).…”

“…CYP4A11 was also found to be responsible for the formation of 17b-DHE, whereas CYP3A was active in EXE oxidation to form 6-hydroxymethylexemestane (Kamdem et al, 2011). UGT2B17 is the major enzyme responsible for the glucuronidation of 17b-DHE, and the UGT2B17 deletion polymorphism has been linked to increased levels of 17b-DHE formation in plasma of women taking EXE (Sun et al, 2010;Luo et al, 2018). Interestingly, whereas drastic decreases in 17b-hydroxy-EXE-17-O-b-D-glucuronide (17b-DHE-Gluc) levels (e.g., up to 29-fold in plasma) were associated with increasing numbers of the UGT2B17 deletion allele in women taking EXE, only a small (1.3-fold) increase in plasma 17b-DHE was observed in the same women (Luo et al, 2018).…”

Hepatic Abundance and Activity of Androgen- and Drug-Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, and Sex

“…Similarly, the PK and anticancer effectiveness of UGT2B17 substrates 17-dihydroexemestane and vorinostat are highly variable (Wong et al, 2011;Chen et al, 2016b). Particularly, the normalized 17-dihydroexemestane and vorinostat levels were 28% and 26% higher, respectively, in subjects carrying the UGT2B17 gene deletion compared with those carrying the reference allele (Wong et al, 2011;Luo et al, 2017). The in vitro glucuronidation rate of 17-dihydroexemestane is significantly decreased (14-fold) in human liver microsomes (HLMs) exhibiting the UGT2B17 deletion genotype versus wild-type UGT2B17 HLMs .…”