Drug metabolism and pharmacokinetics in malnourished children.
Malnutrition is a complex condition in which many deficiencies occur simultaneously. Protein-energy malnutrition is a major public health and clinical problem in paediatric practice that accounts for high child mortality and morbidity. It includes many different clinical syndromes with protean manifestations. The malnourished often have several concomitant diseases; drugs are therefore as widely used as in the well-nourished. The pathophysiological profile in malnutrition can alter pharmacokinetic processes, drug responses and toxicity. This review summarizes the available knowledge on nutrient-drug interactions in malnourished children. Although there is much evidence in the literature that diet and nutritional status are 2 important environmental variables determining the pharmacotoxicological properties of chemicals, there are few data on humans. Recently, intense effort has been initially directed at studying drug kinetics in grade III malnutrition, namely kwashiorkor and marasmus. Studies on drugs and nutrients indicate delayed or decreased absorption, reduced protein binding of several drugs, fluctuations in volume of distribution, altered hepatic oxidative drug biotransformations and conjugations, reduced elimination of conjugates and reduced elimination of renally excreted drugs. The estimated steady-state levels of a few drugs suggest accumulation. Bioavailability problems with certain drugs are due to divergent effects of pharmacokinetic processes. Clinical risk of toxicity appears to be higher in malnourished children. Rehabilitation studies suggest that a number of these pharmacological abnormalities can be reversed. The majority of studies have concentrated on single-dose pharmacokinetics in severely malnourished children. A number of abnormalities seen in drug disposition during the acute phase of malnutrition need to be confirmed for other grades of malnutrition. For practical purposes, it is important to consider steady-state levels and data in mild and moderate forms of growth-retarded children; drug-induced nutritional deficiencies can occur more easily in these populations. Although some of the drugs described in this review have been in use for many years, knowledge on drug response and toxicity is still only approximate. There is at present enough evidence to support monitoring plasma drug concentrations in malnourished children, particularly for those drugs which have dose-dependent kinetics and narrow margins of safety. The metabolism and disposition of xenobiotics seem to vary widely in children with protein-energy malnutrition. Therapeutic inadequacies and toxicities need careful evaluation in malnourished children.