What changes drug metabolism in critically ill patients--III? Effect of pre-existing disease on the metabolism of midazolam.

Liver samples were obtained at hepatectomy from patients with end stage alcoholic liver disease (n = 5), primary biliary cirrhosis (n = 5) and chronic rejection needing retransplantation (n = 5). Normal liver material was also obtained from five organ donors. From these samples microsomes were made containing cytochrome P450 3A. The amount of this enzyme was measured by Western immunoblotting and its function assessed by measuring the rate of production of two metabolites of midazolam, 1-hydroxy midazolam and 4-hydroxy midazolam. There was a wide range in all groups for both the expression and function of this enzyme. Liver tissue affected by cirrhotic disease showed greater preservation of enzyme function than that affected by hepatocellular disease. There was a good correlation between the expression of the enzyme and production of the 1-hydroxy metabolite, but a poor correlation between production of the 4-hydroxy metabolite and expression. This poor correlation may reflect the failure to measure the specific enzyme responsible for producing 4-hydroxy midazolam.