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Published on: March 28, 2017

Association of UGT and CYP genotype-predicted activity with tyrosine kinase inhibitor toxicity

April T Moy1, Lia E D'Angelo, Daniel L Hertz

  • 1Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA.

Pharmacogenetics and Genomics
|August 2, 2026
PubMed

Insights

Genetically predicted enzyme activity did not associate with tyrosine kinase inhibitor toxicity overall. However, reduced UGT1A1 activity increased liver enzyme and hypertension risks, while increased CYP1A2 activity lowered pazopanib toxicity.

Area of Science:

  • Pharmacogenomics
  • Oncology
  • Drug Metabolism

Background:

  • Tyrosine kinase inhibitors (TKIs) are crucial cancer treatments.
  • Patient response and toxicity vary significantly.
  • Genetic variations in metabolic enzymes like UGT1A1, CYP3A4, and CYP1A2 influence drug metabolism and potential adverse events.

Purpose of the Study:

  • To investigate the association between genetically predicted activity of UGT1A1, CYP3A4, and CYP1A2 enzymes and toxicity in patients receiving nilotinib or pazopanib.
  • To explore potential pharmacogenetic markers for optimizing TKI dosing and improving treatment outcomes.

Main Methods:

  • Retrospective pharmacogenetic association study.
  • 117 participants from the Michigan Genomics Initiative who received pazopanib or nilotinib.
  • Clinical data including disease, treatment, and toxicity were collected via medical record review.

Main Results:

  • No significant associations were found between the genetically predicted activity of UGT1A1, CYP3A4, or CYP1A2 and the composite endpoint of severe toxicity or treatment modifications.
  • Secondary analyses revealed that reduced UGT1A1 activity was associated with increased aspartate aminotransferase/alanine aminotransferase and hypertension.
  • Increased CYP1A2 activity was linked to a lower incidence of severe toxicity from pazopanib.

Conclusions:

  • While overall associations were not significant, specific enzyme activities may influence particular TKI toxicities.
  • Reduced UGT1A1 activity may predict increased risk of liver enzyme elevation and hypertension.
  • Increased CYP1A2 activity might be protective against pazopanib toxicity.
  • Further research is needed to validate these findings and explore personalized TKI treatment strategies.
Keywords:
CYP1A2CYP3A4Michigan Genomics InitiativeUGT1A1nilotinibpazopanibpharmacogenetic

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