The Metabolic Activation of Sofosbuvir Is Impaired in an Experimental Model of NAFLD

Simple Summary Steatosis is a disease of the liver characterized by the deposition of lipids in hepatocytes. Although the effect of steatosis on the metabolism of drugs has been investigated, the findings obtained so far are still controversial. We here evaluated the pharmacokinetics of the main inactive metabolite of sofosbuvir, the first direct antiviral agent reaching the market for hepatitis C treatment, called GS-331007. We demonstrated that plasmatic levels of GS-331007 increased significantly in rats with steatosis, whereas the expression of the enzyme UMP-CMPK, responsible for the activation of sofosbuvir to its active metabolite GS-331007-TP, was significantly lower than that of healthy animals. The reduction of UMP-CMPK expression suggests an impairment of sofosbuvir activation, giving a possible explanation for the reduction of its efficacy in patients affected by genotype 3 HCV, which is often associated with liver steatosis. The effect of liver steatosis on drug metabolism has been investigated in both preclinical and clinical settings, but the findings of these studies are still controversial. We here evaluated the pharmacokinetic profile of the main sofosbuvir metabolite GS-331007 in healthy animals and rats with non-alcoholic fatty liver disease (NAFLD) after the oral administration of a single 400 mg/kg dose of sofosbuvir. The plasma concentration of GS-331007 was evaluated by HPLC-MS. The expression of the two enzymes uridine monophosphate-cytidine monophosphate kinase 1 (UMP-CMPK1), and nucleoside diphosphate kinase (ND-PK), responsible for the formation of the active metabolite GS-331007-TP, were measured by qRT-PCR and Western Blot. We demonstrated that in rats with steatosis, the area under the plasma concentration-vs-time curve (AUC) and the peak plasma concentration (C-max) of GS-331007 increased significantly whereas the expression of UMP-CMPK was significantly lower than that of healthy animals. The reduction of UMP-CMPK expression suggests an impairment of sofosbuvir activation to GS-331007-TP, giving a possible explanation for the reduction of sofosbuvir efficacy in patients affected by genotype 3 Hepatitis C virus (HCV), which is often associated with liver steatosis. Furthermore, since GS-331007 plasma concentration is altered by steatosis, it can be suggested that the plasma concentration of this metabolite may not be a reliable indicator for exposure-response analysis in patients with NAFLD.

Automated summary

This study evaluated the effect of liver steatosis on the metabolism of sofosbuvir, a direct antiviral agent used to treat hepatitis C. The results showed that plasma levels of the inactive metabolite GS-331007 increased significantly in rats with steatosis, while the expression of the enzyme UMP-CMPK, responsible for activating sofosbuvir, was significantly lower. This may explain the reduced efficacy of sofosbuvir in patients with liver steatosis.