In vitro and in vivo oxidative metabolism and glucuronidation of anastrozole

Br J Clin Pharmacol. 2010 Dec;70(6):854-69. doi: 10.1111/j.1365-2125.2010.03791.x.


Aims: Little information is available regarding the metabolic routes of anastrozole and the specific enzymes involved. We characterized anastrozole oxidative and conjugation metabolism in vitro and in vivo.

Methods: A sensitive LC-MS/MS method was developed to measure anastrozole and its metabolites in vitro and in vivo. Anastrozole metabolism was characterized using human liver microsomes (HLMs), expressed cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs).

Results: Hydroxyanastrozole and anastrozole glucuronide were identified as the main oxidative and conjugated metabolites of anastrozole in vitro, respectively. Formation of hydroxyanastrozole from anastrozole was markedly inhibited by CYP3A selective chemical inhibitors (by >90%) and significantly correlated with CYP3A activity in a panel of HLMs (r= 0.96, P= 0.0005) and mainly catalyzed by expressed CYP3A4 and CYP3A5. The K(m) values obtained from HLMs were also close to those from CYP3A4 and CYP3A5. Formation of anastrozole glucuronide in a bank of HLMs was correlated strongly with imipramine N-glucuronide, a marker of UGT1A4 (r= 0.72, P < 0.0001), while expressed UGT1A4 catalyzed its formation at the highest rate. Hydroxyanastrozole (mainly as a glucuronide) and anastrozole were quantified in plasma of breast cancer patients taking anastrozole (1 mg day⁻¹); anastrozole glucuronide was less apparent.

Conclusion: Anastrozole is oxidized to hydroxyanastrozole mainly by CYP3A4 (and to some extent by CYP3A5 and CYP2C8). Once formed, this metabolite undergoes glucuronidation. Variable activity of CYP3A4 (and probably UGT1A4), possibly due to genetic polymorphisms and drug interactions, may alter anastrozole disposition and its effects in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anastrozole
  • Antineoplastic Agents, Hormonal / blood
  • Antineoplastic Agents, Hormonal / pharmacokinetics*
  • Breast Neoplasms / blood
  • Chromatography, Liquid / methods
  • Cytochrome P-450 CYP3A / physiology
  • Female
  • Glucuronides / metabolism*
  • Glucuronosyltransferase / physiology
  • Humans
  • In Vitro Techniques
  • Metabolic Networks and Pathways / physiology
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Nitriles / blood
  • Nitriles / pharmacokinetics*
  • Oxidation-Reduction
  • Tandem Mass Spectrometry / methods
  • Triazoles / blood
  • Triazoles / pharmacokinetics*


  • Antineoplastic Agents, Hormonal
  • Glucuronides
  • Nitriles
  • Triazoles
  • bilirubin glucuronoside glucuronosyltransferase
  • Anastrozole
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Glucuronosyltransferase