As with adults, the primary organ responsible for drug metabolism in children is the liver. Although the cy-tochrome P450 system is fully developed at birth, it functions more slowly than in adults. Phase I oxidation reactions and demethylation enzyme systems are significantly reduced at birth. However, the reductive enzyme systems approach adult levels and the methylation pathways are enhanced at birth. This often contributes to the production of different metabolites in newborns from those in adults. For example, newborns metabolize approximately 30% of theophylline to caffeine rather than to uric acid derivatives, as occurs in adults. While most phase I enzymes have reached adult levels by 6 months of age, alcohol dehydrogenase activity appears around 2 months of age and approaches adult levels only by age 5 years.
Phase II synthetic enzyme reactions are responsible for the elimination of endogenous compounds, such as bilirubin, and many exogenous substances. The immaturity of the glucuronidation pathway was responsible for the development of gray baby syndrome (see Chapter 47) in newborns receiving chloramphenicol. Preterm and newborn infants dying of this syndrome developed anemia and cardiovascular collapse because of high blood concentrations of unconjugated chlorampheni-col. The plasma half-life was found to be 26 hours in these patients compared with 4 hours in older children.
Infants and children have a greater capacity to carry out sulfate conjugation than do adults. For example, acetaminophen is excreted predominantly as a sulfate conjugate in children as opposed to a glucuronide conjugate in adults. This enhanced sulfation of acetaminophen, along with decreased metabolism via cytochrome P450 pathways and increased glutathione turnover, are thought to explain the decreased hepatotoxicity caused by this analgesic in children under 6 years of age. Phase II enzyme systems reach adult levels between 3 and 6 months of age.
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