Drugs and altered hepatic biotransformation: Clinical and experimental studies

In recent years basic research has contributed greatly to defining the role of the liver and its subcellular components in drug metabolism, and has drawn attention to various factors which may alter the activity of hepatic drug metabolising enzymes (such as enzyme induction). However, the clinical relevance of much of this information remains to be established. In this thesis I have attempted to explore certain drug-liver interactions, with particular reference to the clinical significance of drug stimulation of hepatic biotransformation, and the effect of liver disease on drug metabolism. Chapter I outlines the evolutionary development of hepatic biotransformation (a more appropriate term than detoxication or drug metabolism since many naturally occurring endogenous and exogenous substrates are metabolised (not necessarily to inactive products) by a microsomal enzyme system of broad specificity) . This process can usefully be considered to occur in two phases, and details of the subcellular localisation and properties of the enzymes involved are reviewed. Rate limiting steps both in vivo and in vitro, and various pharmacological consequences of hepatic biotransformation are also discussed. Chapter II summarises important genetic and environmental factors affecting hepatic biotransformation. Particular attention is paid to the phenomenon of hepatic microsomal enzyme induction. Various direct and indirect methods (morphological, pharmacological and biochemical) used to measure the activity of hepatic microsomal enzymes in man (and thus to determine the presence of the "induced state) are reviewed. These include the merits and disadvantages of the measurement of urinary D-glucaric acid excretion, a technique applied in subsequent clinical studies (Chapters IV and V) to assess enzyme induction. As the liver plays such a central role in the metabolism of both endogenous and foreign compounds, liver disease might be expected to have important consequences for drug metabolism. The conflicting evidence is outlined in Chapter III, together with data obtained from a collaborative study in patients with hepatic cirrhosis, using chlorpromazine as the test drug, and measuring the plasma disappearance and cerebral effects of this phenothiazine. Although no significant difference in plasma clearance of chlorpromazine (compared to normal controls) was found, the cirrhotic group was undoubtedly more sensitive to the sedative effects of this drug. Various mechanisms which might disturb hepatic biotransformation in patients with liver disease are discussed. Pharmacokinetic concepts are used in an attempt to explain the altered sensitivity to sedative drugs which is characteristic of cirrhotics, and a critical appraisal made of previous studies investigating drug metabolism in liver disease. An excellent example of the clinical application of advances in the basic sciences has been provided by attempts to stimulate hepatic biotransformation in man using enzyme inducing drugs, such as barbiturates. This technique has been used most widely in the treatment of various types of jaundice, and is reviewed in Chapter IV. While undoubtedly effective in lowering bilirubin levels, the mechanism of action remains obscure as hepatic enzyme induction is accompanied by several other drug mediated effects on the hepatocyte and whole liver. The results of clinical and animal studies undertaken in an effort to determine the relative importance of enhanced bilirubin conjugation compared to increased choleresis in the reduction of plasma bilirubin levels seen after phenobarbitone administration are presented. While not providing a conclusive answer, they emphasise the importance of species variation in response to hepatic enzyme inducing drugs, and the need for caution before extrapolating results from experiments in animals to man. Additional possible therapeutic applications resulting from enhancement of hepatic biotransformation are considered in Chapter V