Many drugs are known or suspected of having substantial first-pass hepatic metabolism in humans, and have low oral bioavailability on this basis. Hepatic disease might alter (increase) bioavailability by either or both of 2 mechanisms: decreased hepatic extraction due to impaired hepatic drug metabolising activity, or portosystemic shunting. Few studies have examined the effect of liver diseases on bioavailability, and even fewer have attempted to directly measure hepatic extraction of drugs in liver disease. Data are conflicting, with some evidence to suggest that hepatocyte function is preserved in moderate cirrhosis, while other evidence suggests a decrease in hepatic metabolic function. Several studies show relative preservation of systemic clearance in the face of substantial increases in bioavailability, suggesting that the hepatic arterial blood supply of the liver is an important determinant of systemic clearance in cirrhotic patients.Increases in bioavailability and decreases in systemic clearance have multiplicative, rather than additive, effects on area under the plasma concentration-time curve after oral administration. Clinically, there are important implications of these studies. If differences in response between patients with and without liver disease are seen after equivalent intravenous doses of a high clearance drug, the differences may be further accentuated after oral dosing. Delayed toxicity, due to accumulation of high clearance drugs is more likely to occur because of the longer half-life and larger available dose. Physicians should use extra caution in administering high clearance compounds to patients with liver disease.