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Inhibition of SN-38 glucuronidation by gefitinib and its metabolite

Wei Li1, Yafei Xing, Yong Liu

  • 1College of Medicine, Yangzhou University, Yangzhou, 225001, China.

Cancer Chemotherapy and Pharmacology
|April 29, 2015
PubMed

Insights

Gefitinib and its metabolite O-desmethyl-gefitinib inhibit SN-38 glucuronidation via UGT1A1. This drug interaction may increase SN-38 exposure, potentially leading to toxicity in clinical settings.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Clinical Toxicology

Background:

  • Irinotecan is a chemotherapy agent with active metabolite SN-38.
  • Drug interactions can increase SN-38 concentrations, leading to toxicity.
  • Gefitinib is used in cancer treatment and its interactions require study.

Purpose of the Study:

  • To investigate the effects of gefitinib and O-desmethyl-gefitinib (DMG) on SN-38 glucuronidation.
  • To assess the potential clinical implications of this drug interaction.

Main Methods:

  • In vitro studies were conducted to assess SN-38 glucuronidation inhibition.
  • UGT1A1 inhibition was a key focus.
  • In silico prediction was used to estimate clinical effects.

Main Results:

  • Both gefitinib and DMG were identified as potent inhibitors of SN-38 glucuronidation.
  • UGT1A1 inhibition was confirmed as the mechanism.
  • Predicted a 149% increase in SN-38 AUC at high gefitinib doses (700 mg/day).

Conclusions:

  • Gefitinib and DMG significantly inhibit SN-38 glucuronidation.
  • Clinical toxicity due to increased SN-38 exposure is a potential risk at higher gefitinib doses.
  • Findings support the design of clinical studies for optimizing combination therapy.

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