Disposition of a flow-limited drug (lidocaine) and a metabolic capacity–limited drug (theophylline) in liver cirrhosis

Abstract

The plasma clearance after oral administration of a completely absorbed drug that is metabolized by the liver depends on its intrinsic clearance. In cirrhosis the bioavailability of a flow-dependent drug increases because of both portosystemic shunting and hepatocyte dysfunction. A drug with a high extraction ratio, lidocaine, and a drug with a low extraction ratio, theophylline, were administered to 27 patients with cirrhosis and 16 control subjects. We found a significant impairment of both theophylline clearance (p < 0.001) and lidocaine clearance (p < 0.001) and an increase in the lidocaine peak concentration (p < 0.001). The three parameters were significantly correlated with each other. The impairment of theophylline metabolism did not correlate with other indexes of disease severity, whereas lidocaine clearance was lower and lidocaine peak level higher in patients with decompensated cirrhosis and evidence of portal hypertension. Thus impairment in lidocaine disposition, which reflects both hepatocyte dysfunction and portosystemic shunting, correlated closer with the severity of liver disease than did theophylline metabolism.