Abstract

Fulvestrant (Faslodex) is administered by intramuscular injection and is converted into ketone, sulfate, sulfone and glucuronide metabolites. Glucuronidation, catalyzed by 18 members of the UDP-glucuronosyltransferase (UGT) enzyme family, plays a major role in the elimination of natural estrogens. The present study was aimed at identifying and characterizing human UGT enzymes involved in the glucuronidation of this antiestrogen as well as other synthetic estrogen derivatives with aliphatic chains on the E₂ molecule. In contrast to E₂, which is conjugated by UGT1A1, -1A3, -1A8, -1A10, and -2B7, fulvestrant is glucuronidated by UGT1A1, -1A3, -1A4, and -1A8. The four UGT1A-fulvestrant conjugating enzymes glucuronidate this substrate at position 3, whereas only UGT1A8 also produces fulvestrant-17-glucuronide. For E₂, only UGT1A3 and UGT2B7 are capable to conjugate at 17-hydroxyposition. These observations indicate that addition of an aliphatic chain to the E₂ molecule modifies the specificity of the UGT enzymes toward the C₁₈ molecules. To further investigate the specificity of these enzymes, a series of E₂ derivatives with aliphatic or phenyl chains at position 2, 7α, and 11β was also tested for its conjugation with human UGT enzymes. It was observed that, in addition to UGT1A3, UGT1A1 and UGT1A8 also played important roles for the glucuronidation of these compounds. This suggests that the basic structure of E₂ is one of the major determinants for the glucuronidation catalyzed by this group of enzymes. Considering the high level of UGT1A3 and -1A4 expression in the gastrointestinal tract and mammary gland, our results suggest that fulvestrant can be inactivated both in intestine and in its target tissue.