Developmental Aspects of Drug Metabolism in Children

Abstract

The goal of rational drug therapy is to produce a desired pharmacological response in an acceptable and predictable manner while minimizing the occurrence of undesired events. In the context of pediatric pharmacotherapy, the process of maturation has been demonstrated to markedly influence drug disposition and thus, contributes significantly to the variability observed in this patient population. The cytochromes P450 are quantitatively the most important enzymes responsible for oxidative drug metabolism. The development of functional P450 activity is traditionally viewed as being limited in newborns but increasing in the first year of life to levels in toddlers and older children that generally exceed adult capacity. It is becoming apparent, however, that not all P450s share the “traditional” developmental profile and that the contribution of individual pathways to overall drug biotransformation will change with age. Since altered drug biotransformation can contribute significantly to therapeutic failure, that is, graft rejection with cyclosporin and inadequate serum concentrations of antineoplastics, and possibly drug toxicity, characterization of drug biotransformation pathways during development is essential for optimum treatment. The development of acceptable, preferably noninvasive, phenotyping procedures for all age ranges including newborns, infants, and older children will be a major challenge for investigators but will hopefully be rewarded by improved pediatric pharmacotherapy.