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Fulvestrant (Faslodex™) is a pure antiestrogen that is effective in treating estrogen receptor-(ER) positive breast cancer tumors that are resistant to selective estrogen receptor modulators such as tamoxifen. Clinical trials investigating the utility of adding fulvestrant to other therapeutics have not been shown to affect cytochrome P450-mediated metabolism. Effects on phase II metabolism and drug resistance have not been explored. This study demonstrates that fulvestrant up regulates the expression of UDP glucuronosyltransferase 1A4 ( UGT1A4 ) >2.5- and >3.5-fold in MCF7 and HepG2 cells, respectively. Up regulation occurred in a time- and concentration-dependent manner, and was inhibited by siRNA silencing of ERα. Fulvestrant also up regulates multidrug resistance-associated proteins (MRPs). There was an up regulation of  MRP 2 (1.5- and 3.5-fold), and  MRP 3 (5.5- and 4.5-fold) in MCF7 and HepG2 cell lines, respectively, and an up regulation of  MRP1  (4-fold) in MCF7 cells.  UGT1A4  mRNA up regulation was significantly correlated with UGT1A4 protein expression, anastrozole glucuronidation,  ERα  mRNA expression and  MRP  mRNA expression, but not with ERα protein expression. Genetic variants in the  UGT1A4  promoter (-163A, -217G and -219T) reduced the basal activity of  UGT1A4  by 40-60%.  In silico  analysis indicated that transcription factor  c-Myb  binding capacity may be affected by these variations. Luciferase activity assays demonstrate that silencing  c-Myb  abolished UGT1A4 up regulation by fulvestrant in promoters with the common genotype (-163G, -217 T and -219C) in MCF7 cells. These data indicate that fulvestrant can influence the disposition of other UGT1A4 substrates. These findings suggest a clinically significant role for  UGT1A4  and  MRP s in drug efficacy.

Fulvestrant up regulates UGT1A4 and MRP s through ERα and c-Myb pathways: a possible primary drug disposition mechanism