Abstract 1878: Upregulation of UGT1A4 by fulvestrant: A potential elimination mechanism of anastrazole in breast cancer treatment
Authors: Vineetha Koroth Edavana, Ishwori B. Dhakal, Suzanne Williams, Susan A. Kadlubar
Journal: Cancer Research (2012)

Abstract The pure antiestrogen, fulvestrant (Faslodex®) has been approved for use in the treatment of postmenopausal patients with hormone-receptor positive metastatic disease. It has been postulated that the combination of an aromatase inhibitor with a pure antiestrogen could provide therapeutic advantages over the administration of an aromatase inhibitor alone. The effect of co-administration of these drugs on Phase I and Phase II metabolism (i.e. glucuronidation) have not been explored. The role of pharmacogenetics in clinical benefit and overall survival in patients receiving anastrozole and fulvestrant is unexplored. In this study, we demonstrated that fulvestrant up-regulates expression of UDP glucuronosyltransferase (UGT) 1A, the major enzyme responsible for the direct conjugation and subsequent elimination anastrozole. Endogenous mRNA expression levels of UGT1A4 in HepG2 cells were induced 4.2-fold by fulvestrant treatment in the ERα-expressing cell line. In vitro assays using liver microsomal specimens from individual subjects demonstrated 163 fold variability in anastrazole glucuronidation. Anastrazole glucuronodation was correlated (r = 0.977, p &amp;lt;0.0001) with lamotrigine glucuronidation, a diagnostic substrate for UGT1A4. We also found a significant correlation between anastrazole glucuronidation and UGT1A4 mRNA expression levels in these HLMs (r = 0.978, p &amp;lt;0.0001). We also examined whether UGT1A4 promoter SNPs were associated with the observed interindividual variability in anastrozole glucuronidation. Microsomes from the subjects with mutated heterozygous UGT1A4 promoter SNPs 36G&amp;lt;A and SNPs 217 T&amp;lt;G exhibited a significantly higher activity than the microsomes from the subjects with homozygous wild type UGT1A4 promoter SNP 36G&amp;lt;A and SNP 217 T&amp;lt;G. On the other hand, microsomes from the subjects with homozygous wild typeUGT1A4 promoter SNPs 219C&amp;lt;T and SNPs 163G&amp;lt;A exhibited significantly higher activity when compared with microsomes from the subjects with mutated heterozygous UGT1A4 promoter SNPs 219C&amp;lt;T and SNPs 163G&amp;lt;A. These in vitro studies indicate that fulvestrant administration could influence the disposition of anastrazole in combination therapy of aromatase inhibitor with a pure antiestrogen by up regulating the phase II metabolizing enzyme UGT1A4. Our data also suggest that the UGT1A4 promoter polymorphisms may be associated with altered rates glucuronidation and detoxification of anastrazole in vivo. Further studies are needed to assess the complete effects of fulvestrant administration on the disposition of drugs that are substrates of UGT1A4. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1878. doi:1538-7445.AM2012-1878