Cancer Chemotherapy and Pharmacology

, Volume 82, Issue 5, pp 795–802 | Cite as

In vitro UGT1A1 inhibition by tyrosine kinase inhibitors and association with drug-induced hyperbilirubinemia

  • Hisham Qosa
  • Brittany R. Avaritt
  • Neil R. Hartman
  • Donna A. VolpeEmail author
Original Article



Hyperbilirubinemia has been observed in patients treated with tyrosine kinase inhibitor (TKI) drugs. Therefore, it would be beneficial to understand whether there is a relationship between inhibition of uridine-5′-diphosphate glucuronosyltransferase (UGT) 1A1 activity and observed bilirubin elevations in TKI drug-treated patients. UGT1A1 is responsible for the glucuronidation of bilirubin which leads to its elimination in the bile.


To examine this question, an in vitro glucuronidation assay was developed to determine the inhibitory effect of TKI drugs employing human liver microsomes (HLM) with varying UGT1A1 activity. Utilizing β-estradiol as the UGT1A1 probe substrate, 20 TKI drugs were evaluated at concentrations that represent clinical plasma levels. Adverse event reports were searched to generate an empirical Bayes geometric mean (EGBM) score for clinical hyperbilirubinemia with the TKI drugs.


Erlotinib, nilotinib, regorafenib, pazopanib, sorafenib and vemurafenib had IC50 values that were lower than their clinical steady-state Cmax concentrations. These TKI drugs had high incidences of hyperbilirubinemia and higher EBGM scores. The IC50 values and Cmax/IC50 ratios correlated well with EBGM scores for hyperbilirubinemia (P < 0.005). For the TKI drugs with higher incidence of hyperbilirubinemia in Gilbert syndrome patients, who have reduced UGT1A1 activity, six of eight had smaller ratios in the low UGT1A1 activity microsomes than the wild-type microsomes for drugs, indicating greater sensitivity to the drugs in this phenotype.


These results suggest that in vitro UGT1A1 inhibition assays have the potential to predict clinical hyperbilirubinemia.


Tyrosine kinase inhibitors Hyperbilirubinemia UGT1A1 Polymorphisms 



Drs. Qosa and Avaritt were supported by an appointment to the Research Participation Program at CDER, administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the US Department of Energy and the FDA. Special thanks to Dr. Peter Schotland for the Empirica Signal search.


The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency endorsement, determination or policy.

Compliance with ethical standards

Conflict of interest

All the authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

280_2018_3665_MOESM1_ESM.docx (63 kb)
Supplementary material 1 (DOCX 63 KB)


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Copyright information

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection 2018

Authors and Affiliations

  • Hisham Qosa
    • 1
  • Brittany R. Avaritt
    • 1
    • 2
  • Neil R. Hartman
    • 1
  • Donna A. Volpe
    • 1
    Email author
  1. 1.Office of Clinical Pharmacology, Center for Drug Evaluation and ResearchFood and Drug AdministrationSilver SpringUSA
  2. 2.Office of Generic Drugs, Center for Drug Evaluation and ResearchFood and Drug AdministrationSilver SpringUSA

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