Abstract
BackgroundSorafenib, 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.MethodsSorafenib 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.ResultsThe 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.ConclusionsSorafenib metabolism was remarkably decreased in THLMs. This result was associated with the down regulation of the protein expression of CYP3A4 and UGT1A9.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common hepatic malignancies in regions where chronic hepatitis or liver diseases are prevalent, such as in China [1,2]
Given that M6 and M8 are not detectable by the present analytical method, we determined the formation of sorafenib metabolites M1 to M5 mediated by CYP3A4 and M7 mediated by UGT1A9 in the pooled and individual THLMs, NHLMs, and CHLMs
The rate of CYP3A4-mediated oxidation of sorafenib was remarkably decreased in the pooled THLMs compared with those in the pooled NHLMs and pooled CHLMs (Figures1A–1E)
Summary
Hepatocellular carcinoma (HCC) is one of the most common hepatic malignancies in regions where chronic hepatitis or liver diseases are prevalent, such as in China [1,2]. Sorafenib metabolism occurs primarily in the liver by cytochrome P450 (CYP) 3A4-mediated oxidation and uridine diphosphate glucuronosyl transferase (UGT) 1A9-mediated glucuronidation [2]. Sorafenib N-oxide (M2) accounts for ,17% of the circulating analytes in the plasma and is the major CYP 3A4 metabolite. A previous study has reported that plasma sorafenib concentration is increased by inhibiting CYP3A4 in combination with felodipine in a patient with HCC [11]. Changes in sorafenib metabolism by altering CYP3A4 or UTG1A9 activity may affect its clinical effects and sorafenib-induced toxicity. 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. The metabolism characteristic of sorafenib has not been systematically determined in HCC patients
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