Impact of Metabolizing Enzymes on Drug Response of Endocrine Therapy in Breast Cancer

Pilar H Saladores; Jana C Precht; Werner Schroth; Hiltrud Brauch; Matthias Schwab


Expert Rev Mol Diagn. 2013;13(4):349-65. 

In This Article


Anastrozole metabolism consists mainly of hydroxylation to OH-anastrozole by CYP3A4 with subsequent glucuronidation to glucuronide-OH-anastrozole. Another metabolic pathway is the direct N-glucuronidation via UGT1A4.[131] Triazol, the major cleavage product, is pharmacologically inactive.[132] Plasma levels of anastrozole and its metabolite levels show substantial interindividual variability as demonstrated in 191 postmenopausal women with early breast cancer.[133] Whether variability of anastrozole pharmacokinetics is related to incomplete aromatase inhibition and subsequent residual estrogen levels under therapy is currently unknown. UGT1A4 is polymorphically expressed[134,135] and therefore the impact of UGT1A4 variants including the alleles *2 (rs6755571, 70C>A, P24T) and *3 (rs2011425, 142T>G, L48V) on the in vitro metabolism of anastrozole has been investigated. No significant effects were found,[131] which has been recently confirmed.[136] Of interest, three polymorphisms in the UGT1A4 promoter region (-163G>A, -217T>G, -219C>T) were shown to influence anastrozole N-glucuronidation activity in vitro.[136]

Although it has been shown that concurrent tamoxifen therapy reduces anastrozole plasma levels by 27%, putatively by CYP3A4 induction,[82,137] no change of plasma levels of anastrozole and hydroxyanastrozole was observed in a small study of nine women with concomitant intake of simvastatin, another known CYP3A4 substrate.[138] Thus, it is presently unclear whether a CYP3A4-related drug–drug interaction affects anastrozole metabolism and efficacy. Altogether, the available knowledge on anastrozole's DME pharmacogenetics is quite limited and awaits further investigation.