The goal of rational drug therapy is to produce a desired pharmacological response in an acceptable and predictable manner while minimizing undesired events. With respect to drug distribution (i.e. pharmacokinetics) and metabolism (i.e. biotransformation), children are not simply small adults. The biotransformation pathways in children are neither static over time, nor progress in a linear manner from fetal life through neonatal life and then into childhood, adolescence, and adulthood. In order to avoid therapeutic failure or unwanted toxicity, the rate of these biotransformations with respect to developmental state must be appreciated. While the ontogeny of Phase I pathways such as CYP2D6 and CYP3A4 over the first year of life has been studied, the only Phase II enzyme similarly studied is NAT2 which represents only a small proportion of Phase II biotransformations. APAP is one of the most commonly utilized pharmaceutics in pediatrics. Moreover, in a single therapeutic dose, undesired side effects are minimal. APAP is metabolized by three Phase II biotransformations {i.e. sulfotransferase (SULT), glutathione-S-transferase (GST), and glucuronosyltransferases (UGT)}, which represent three of the most important, both qualitative and quantitative, Phase II reactions. While neonatal studies indicate that, they have less absolute phase II activity and reduced UGT activity relative to SULT activity. To date, there is no in vivo data, which define the changes in activity of these important pathways during the first year of life. The longitudinal assessment of the metabolic ratio of APAP and its metabolites will provide this important information. The information gained from general proposal may also be applied to other important drugs metabolized by these pathways such as zidovudine, morphine, and lorazepam.
