Drug Metabolism and Pharmacokinetics in Malnutrition

Abstract

Malnutrition is usually complex, many deficiencies occurring simultaneously. Changes occur in almost every organ of the body. Apart from the pathophysiological changes which occur in protein-calorie malnutrition, vitamin, mineral and trace element deficiency is accompanied by diverse metabolic changes in tissues. As a consequence there is large potential for alteration of drug response in malnutrition, not only because of possible changes in drug kinetics but also because of changes in tissue uptake and localisation of drugs and potential alteration in drug-receptor interactions. The risk of susceptibility to drug-induced damage may also be increased. The functional status of the gastrointestinal tract is markedly altered in malnourished individuals and as a consequence the rate and extent of drug absorption is likely to be altered. First pass metabolism (intestinal and hepatic) is also likely to be altered. The profile of plasma proteins is considerably changed in malnourished individuals. In most cases, there is hypoalbuminaemia, the degree varying with the severity of malnutrition. Globulins however, are elevated, particularly in cases of infection. Lipoproteins are also reduced in states of malnutrition but there is no information on α₁-acid glycoproteins, which bind basic drugs. Malnutrition, by altering the total body water, body composition and drug binding can lead to changes in the volume of distribution of a drug, depending on its physicochemical properties and its ability to bind to macromolecules. Although electronmicroscopc studies indicate changes in endoplasmic reticulum, liver function in malnutrition seems to be generally well preserved. However, biotransformation of drugs may be altered due to changes in drug metabolising hepatic enzyme activity, alteration in drug binding characteristics of proteins and the significant metabolic and hormonal changes in malnutrition. There may be abnormalities in biliary excretion which may affect drug elimination, at least in severe forms of protein-calorie malnutrition. Severe malnutrition can lead to changes in cardiac and renal function. These changes may be indirectly responsible for alterations in excretion mechanisms. Malnutrition can lead to changes in renal function, although this may not be a uniform change and there are very little data on renal excretion mechanisms and their relationship to drug elimination in malnutrition. Cardiac function also seems to be affected in malnutrition, particularly in children. There is reduction in cardiac output and prolonged circulation time; changes which may indirectly be responsible for decreased renal and hepatic blood fiow. Animal studies reveal that a number of macro- and micronutrient deficiencies can result in alteration in the rate of drug metabolism. Deficiencies in proteins, dietary fat, minerals and vitamins have all been shown to influence the activity of the mixed function oxidases. However, nutritional-pharmacological interactions in human populations are not as simple as observed under experimental conditions where most of the procedures are standardised and the number of variables minimised. A wide variety of environmental factors and complex multiple nutritional deficiencies react and modify nutritional-pharmacological inter-relationships in a human population. There are very few systematic studies of drug kinetics and drug response in malnutrition states in human populations. There is some evidence that absorption of oral tetracycline might be defective, but intramuscular penicillin and streptomycin seem to be absorbed adequately. The volume of distribution of tetracycline is markedly reduced in undernourished individuals. Although plasma albumin binding of a number of drugs has been shown to be reduced in malnourished individuals, with drugs such as tetracycline, phenylbutazone and sulphadiazine there is an increased rate of elimination. This is most probably due to increased amounts of free drug being available for metabolism. Studies of drug biotransformation in malnourished individuals are also as yet inadequate, but there have been a few reports of decreased rates of metabolism with drugs such as chloroquine, tetrachlorethylene and chloramphenicol. Observations on antipyrine pharmacokinetics in protein calorie malnutrition, anaemia, mineral deficiency and on experimental manipulation of proteins and carbohydrates in the diet, indicate that mixed function oxidases can be altered. However, the clinical significance of such findings are yet to be evaluated. The role of nutritional factors in development of cancer has attracted considerable attention. Some studies suggest that nutrition, cancer and drug metabolism (rate of hydroxylation) may be closely interlinked. Evaluation of drug kinetics and drug response in malnutrition must be studied systematically with a range of drugs of different physicochemical and pharmacokinetic properties. The relationship of drug kinetics, particularly drug metabolism, in various deficiency disorders to other environmental factors should also be established.