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 (Cmax) 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.