Pharmacokinetics of drugs in liver disease

Pharmacokinetics is the study of the relationships between the drug dosage regimen and the changes in drug concentration over time. Typically, concentrations are measured in blood, serum or plasma, and the concentration-time profile is described by a series of equations. 

Comparisons of drug pharmacokinetics in hepatic disease have often been based on classifications of mild, moderate or severe disease, 

There are three fundamental processes that determine drug dosage regimens absorption, distribntion and elimination. Three pharmacokinetic parameters are associated with these processes bioavailability (absorption), volume of distribution (distribution and elimination) and clearance (elimination). 

Bioavailability is defined as the extent - and sometimes also the rate -of drug absorption. For oral therapy, absolute bioavailability is usually determined by comparing the area under the concentration-time curve (AUC) after an oral dose with that after an intravenous dose. Assuming clearance is constant, bioavailability is defined as the ratio of oral to intravenous AUC, corrected for dose, and is expressed as a proportion or a percentage. For example, an oral bioavailability of around 20% means that an oral dose of 100 mg would achieve an exposure equivalent to that of an intravenous dose of 20 mg. For some drugs with low bioavailability due to a high first-pass metabolism, oral dose requirements may be lower in patients with severe hepatic disease due to a reduction in first-pass metabolism in the liver and consequent increase in bioavailability [1]. In contrast, reduced bioavailability of lipophilic drugs may occur in cholestasis and has been reported with ciclosporin, particularly with early formulations [5]. 

Volume of distribution (V) is the apparent volume that relates the amount of drug in the body (A) to the measured concentration (C). It is often used to calculate a loading dose. 

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T. F. Blaschke, Protein binding and kinetics of drugs in liver disease, Clin. Pharmacokinet, 2, 32-44 (1977). 

A decrease in the concentration of albumin (in liver disease, nephrotic syndrome, poor general condition) leads to altered pharmacokinetics of drugs that are highly bound to albumin. 

Based on their pharmacokinetic profile alone, the safest statins in chronic compensated liver disease and a history of decompensation are prohahly pravastatin and rosnvastatin. However, clinical experience with rosnvastatin in liver disease is lacking, and so it cannot be recommended. In addition, the true rate of post-marketing adverse drug reactions is not yet clear. Pravastatin is therefore the drug of choice in these patients, where treatment is deemed necessary. It should, however, be avoided in acute episodes until liver function or transaminases stabilise/return to normal. 

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