Liver function tests and elimination of drugs in man

Abstract

The intensity and duration of a drug’s action is dependent on its rate of elimination. For many compounds this process takes place in the liver. Therefore the characterisation of liver function is important for a safe and effective drug treatment. Alterations in liver function can intensify or diminish the therapeutic and toxic effects. From a prospective drug surveillance study of 1280 patients the frequency of adverse drug reactions was higher in 333 patients with clinical and/or histopathological evidence of liver cirrhosis than in 188 with other liver diseases (p〈0.01) and than in 759 patients without liver disease (p〈0.0001). Side effects were more common for drugs biotransformed by the liver [10]. The large, well known interpatient variability in the response to a standard dose might be, at least partially, due to differences in liver function. Consequently, in recent years many attempts were made to individualize drug therapy based upon pharmacokinetic considerations. As a result of these pharmacokinetic studies it became apparent that many factors influence the hepatic elimination of drugs, such as genetic constitution, environment (pollutants), nutrional status, age, sex, smoking habits or concomitantly given drugs. Various disease states, which alter the protein bindung or cardiac output, can also influence the disposition of drugs. Liver function varies widely within any diagnosed group of patients. Difficulties also occur in the selection of the correct and comparable control individuals. Many investigators have studied changes in the half-life (T _½) under the assumption that this parameter directly reflects drug metabolism or excretion by the liver. While this may indeed be a correct presumption for a few drugs with specific characteristics it is not generally valid. This is because T _½ is dependent on both the total body clearance ($\overline {Cl}$) of the drug and its apparent distribution volume (Vd _β ): ${T_{1/2(\beta )}} = \frac{{0.693 \times V{d_\beta }}}{{\overline {Cl} }}$ Physiological variables, such as hepatic blood flow, drug metabolizing activity/capacity and plasma binding also determine the elimination of drugs. Certain diseases may affect more than one of these determinants, and thereby exaggerate or dampen any effect associated with altered hepatocyte function alone. The clearance concept is of particular value in this regard, since it is independent of distributional changes and is a direct measure of the efficiency of drug removal from a biological fluid. Pharmacokinetically, total body clearance ($\overline {Cl}$) can be calculated, independent of the compartment model used, by the equation: $\overline {Cl} = \frac{{i.\nu .dose}}{{AU{C_{0 \to \infty }}}}$ Physiologically, $\overline {Cl}$ may be defined relative to the hepatic blood flow Q and the extraction ratio E, which is dependent on the arterial (c _a ) and venous (c _v ) drug concentration across the organ: $\overline {Cl} = Q \times EwithE = \frac{{{c_a} - {c_v}}}{{{c_a}}}$ If only the liver is involved in the elimination of the drug, $\overline {Cl}$ represents the hepatic clearance (Cl_H). In these considerations it is important that clearance is based upon blood concentrations. It is usually assumed that only the unbound drug can be cleared by the liver. If this is true, and since this fraction can be altered in some patients, it may be more appropriate to consider the clearance of free drug.