Abstract 1305: Fulvestrant induces the expression/activity of UGT1A4 in HepG2 cells: potential interactions with other therapeutic agents

Abstract

Abstract Fulvestrant (Faslodex™) is a pure antiestrogen that has been shown to be effective in treating estrogen receptor (ER) positive tumors that are resistant to selective estrogen receptor modulators (SERMs) such as tamoxifen. Currently, clinical trials investigating the utility of adding fulvestrant to other therapeutics are being conducted. While co-administration of these drugs has not been shown to affect cytochrome P450-mediated metabolism of either drug, effects of co-administration on Phase II metabolism (i.e. glucuronidation) have not been explored. We demonstrated that fulvestrant up-regulates expression of UDP glucuronosyltransferase (UGT) 1A4, the major enzyme responsible for the direct conjugation and subsequent elimination of many therapeutic drugs. Endogenous mRNA expression levels of UGT1A4 in HepG2 cells were induced 4.5-fold by fulvestrant treatment in this ERα-expressing cell line. Treatment with fulvestrant upregulated UGT1A4 in a time- (0-72 hours) and concentration-(0-250 nM) dependent manner and silencing ERα with specific siRNA abolished UGT1A4 up regulation. The role of a Sp1 binding site (−1906 to -1901 base pairs), known to be critical for the induction of UGT1A4 transcriptional activity by estradiol, was examined in relation to fulvestrant-mediated induction of UGT1A4. Electrophoretic mobility shift assays were performed using these nuclear extracts and UGT1A4/Sp1 probe. Fulvestrant-treated HepG2 nuclear extract formed multiple shifted bands that appear to represent homomultimeric complexes of Sp1 with UGT1A4/Sp1 probe. This binding ability was partially blocked by mithramycin, a known inhibitor of Sp1 binding to DNA. While these in vitro assays indicate that fulvestrant administration could influence the disposition of other UGT1A4 substrates, the clinical significance of these findings is unclear. Further studies are needed to assess the effects of fulvestrant administration on the disposition of drugs that are substrates of UGT1A4, including anastrozole, clozapine, imipramine, irinotecanl, amotrigine, meperidine, midazolam, nicotine, olanzapine, SN-38 and tamoxifen. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1305. doi:10.1158/1538-7445.AM2011-1305</jats:p