Clinical pharmacokinetics in patients with liver disease.

From considerations of hepatic physiology and pathology coupled with pharmacokinetic principles, it appears that altered drug elimination in liver disease may result from the following mechanisms: reduction in absolute cell mass, in cellular enzyme content and/or activity, in portal vein perfusion due to extrahepatic/intrahepatic shunting, or of portal perfusion of hepatocyte mass due to decreased portal flow or sinusoidal perfusion; increase in arterial perfusion relative to portal perfusion; preferential perfusion of the sinusoidal midzone and terminal zones by arterioles; potential for direct mixing of arterial blood within the space of Disse; reduced exchange across the endothelial lining; and impaired diffusion within the space of Disse. In general, oxidative drug metabolism is impaired in liver disease and the degree of impairment of oxidisation differs between drugs but correlates best with the degree of sinusoidal capillarisation, i.e. the degree of access of the drug from the sinusoid to the hepatocyte. Drug conjugation appears to be relatively unaffected by liver disease, whereas elimination by biliary excretion correlates best with the degree of intrahepatic shunting and not with sinusoidal capillarisation. As the latter should impair hepatocyte access of all compounds similarly, a potentially important mechanism could be impaired access of oxygen to hepatocytes as oxidative metabolism is much more sensitive to oxygen supply than are conjugation or biliary excretion. This suggests a potentially important therapeutic role for agents which increase the hepatic oxygen supply. Useful adjunctive strategies may also derive from the oxygen limitation hypothesis. Anaemia should be targeted as a critically important variable, as should oxygen-carrying capacity, i.e. modification of the smoking habit. Additionally, enzyme inducers such as barbiturates may be used if overriding hypoxic constraints are removed by oxygen supplementation. Agents likely to seriously compromise arterial perfusion of the hepatic vascular bed should be avoided, e.g. those causing postural hypotension or vasospasm. Vasodilators can be used to actively promote arterial perfusion. While the effect of liver disease on drug handling is highly variable and difficult to predict, there are well recognised principles for modifying dosage. These include halving the dose of drugs given systemically (or of low clearance drugs given orally) and a 50 to 90% reduction in the dose of drugs with a high hepatic clearance given orally. Changes in the pharmacodynamic effects of drugs (either alone or in addition to pharmacokinetic changes) can also be profound, and awareness of this possibility should be increased.