Sorafenib metabolism is significantly altered in the liver tumor tissue of hepatocellular carcinoma patient

PLoS One. 2014 May 5;9(5):e96664. doi: 10.1371/journal.pone.0096664. eCollection 2014.


Background: Sorafenib, the drug used as first line treatment for hepatocellular carcinoma (HCC), is metabolized by cytochrome P450 (CYP) 3A4-mediated oxidation and uridine diphosphate glucuronosyl transferase (UGT) 1A9-mediated glucuronidation. Liver diseases are associated with reduced CYP and UGT activities, which can considerably affect drug metabolism, leading to drug toxicity. Thus, understanding the metabolism of therapeutic compounds in patients with liver diseases is necessary. However, the metabolism characteristic of sorafenib has not been systematically determined in HCC patients.

Methods: Sorafenib metabolism was tested in the pooled and individual tumor hepatic microsomes (THLMs) and adjacent normal hepatic microsomes (NHLMs) of HCC patients (n = 18). Commercial hepatic microsomes (CHLMs) were used as a control. In addition, CYP3A4 and UGT1A9 protein expression in different tissues were measured by Western blotting.

Results: The mean rates of oxidation and glucuronidation of sorafenib were significantly decreased in the pooled THLMs compared with those in NHLMs and CHLMs. The maximal velocity (Vmax) of sorafenib oxidation and glucuronidation were approximately 25-fold and 2-fold decreased in the pooled THLMs, respectively, with unchanged Km values. The oxidation of sorafenib in individual THLMs sample was significantly decreased (ranging from 7 to 67-fold) than that in corresponding NHLMs sample. The reduction of glucuronidation in THLMs was observed in 15 out of 18 patients' samples. Additionally, the level of CYP3A4 and UGT1A9 expression were both notably decreased in the pooled THLMs.

Conclusions: Sorafenib metabolism was remarkably decreased in THLMs. This result was associated with the down regulation of the protein expression of CYP3A4 and UGT1A9.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Cytochrome P-450 CYP3A / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Glucuronosyltransferase / metabolism
  • Humans
  • Liver / drug effects
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Middle Aged
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacokinetics
  • Niacinamide / therapeutic use
  • Phenylurea Compounds / pharmacokinetics*
  • Phenylurea Compounds / therapeutic use
  • Reproducibility of Results
  • Sorafenib
  • UDP-Glucuronosyltransferase 1A9


  • Antineoplastic Agents
  • Phenylurea Compounds
  • UGT1A9 protein, human
  • Niacinamide
  • Sorafenib
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Glucuronosyltransferase
  • UDP-Glucuronosyltransferase 1A9

Grant support

This work was supported in part by the Key International Joint Research Project of National Natural Science Foundation of China (Grant No. 81120108025) and the Science and Information Technology of Guangzhou (Grant No. 2011Y1-00017-6). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.