Phenotyping of Drug Metabolism in Infants and Children: Potentials and Problems

Abstract

Genetic polymorphism in drug-metabolizing enzymes is a predominant cause of variability in drug metabolism, along with physiologic, pathophysiologic, and environmental factors (Table 1). Such polymorphisms are of interest from a basic biomedical, as well as a clinical, point of view, because differences in treatment outcome and adverse drug reactions have been associated with the different phenotypes. View this table: Table 1. Causes of Variation in Drug Elimination Increased knowledge in this field should also be of great interest in pediatric drug therapy. However, there is almost no information about the maturation of polymorphic traits during ontogenesis. This issue has therapeutic implications in pediatrics, first, because several drug substrates of the polymorphic enzymes also are used in infants and children, and second, because for many such drugs, the treatment results may not be monitored by objective param-eters. A number of polymorphisms in drug metabolizing enzymes have been discovered in the last few decades (Table 2). The cytochrome P450 (CYP) family is the major enzyme system for oxidation of drugs. The clinically most important polymorphisms in this family include the debrisoquine/sparteine type in the CYP2D6 enzyme and the mephenytoin type in the CYP2C19 enzyme. They are based on detrimental mutations in the enzyme genes. Pharmacogenetic polymorphisms also have been described in phase II enzymes, eg, N -acetyl transferase, which was among the first to be discovered. Other polymorphisms have been described for members of the glutathione S -transferase enzyme family, but the clinical importance of these for drug therapy is not fully understood. View this table: Table 2. Some Polymorphisms in Drug-metabolizing Enzymes This polymorphism is inherited as an autosomal recessive trait.1 Homozygous mutated individuals are denoted as poor metabolizers (PM) and are deficient in their …