The effect of progressive liver cirrhosis on drug metabolism in a precision cut liver slices (PCLS) model

Liver cirrhosis is known to reduce the metabolic capacity of the liver. Administration of Sorafenib, which is registered for the treatment of hepatocellular carcinoma, in patients with cirrhosis leads to prominent side effects. This has however not extensively been studied due to the severe complications of the treatment during clinical studies. In the current study the primary goal was to investigate whether liver cirrhosis is associated with diminished drug metabolising capacity, especially Sorafenib, using the precision-cut liver slices (PCLS) model. To this end liver tissue from 3 control and 3 fibrotic rats, and 5 control and 5 humans with liver cirrhosis was included. The viability, metabolic capacity for model drugs, effect of treatment with Sorafenib on viability and on mRNA expression of the PDGFβ receptor in PCLS incubated with and without Sorafenib was analysed. In conclusion, we identified three important findings. Firstly, human control and cirrhotic PCLS were viable up to 24 hours. Moreover, incubation with up to 2 µM of Sorafenib can be considered as non-toxic, Secondly, in this study there is no significant difference between the drug metabolism capacity of control and cirrhotic liver tissue from human. Thirdly incubation of rat PCLS for 48 hours with 2 µM Sorafenib showed significant reduction of the PDGFβ receptor expression, which indicates that Sorafenib is still effective. However, more inclusions are mandatory to support this conclusion