V. Edavana, I. Dhakal, Suzanne P Williams
Apr 15, 2012
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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 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