takes for half the drug to be excreted from the body, which is one of the determinants for choosing a dosing schedule, e.g., once a day versus three times a day).

For example, in newborns, the enzyme glucuronyl transferase, which metabolizes the drug chloramphenicol, has a very low level of activity. When chloramphenicol was first used in newborns in the 1950s, the dose was extrapolated from adult doses without knowledge of the drug’s metabolic pathway. At the time, it was also not possible to determine concentrations of drugs in serum because of a lack of technology to measure drug concentrations in the small quantities of blood that can be safely extracted from neonates, infants, and small children. With the doses selected by individual pediatricians, the drug reached much higher concentrations in infants than in adults, resulting in death from the “gray baby syndrome” (see, e.g., Weiss et al., 1960). The technologies available today allow medicines like chloramphenicol to be more fully evaluated before they are used with pediatric patients.

The rates of maturation of drug clearance pathways after the neonatal period are highly variable and relate to the specific metabolic enzymes or kidney mechanisms that are responsible for drug excretion. (Other variables such as disease state and drug-drug interactions can also influence drug clearance.) Research shows that although neonates excrete many medicines much more slowly than adults, prepubertal children often excrete drugs much more rapidly than adults. Thus, although overdosing based on the extrapolation of doses for adults to doses for neonates is likely, underdosing of children is common.

During puberty, drug clearance and half-life move toward adult levels (Goodman et al., 2001). The changes during this period depend on the specific pathways of clearance of a given medicine (i.e., which enzymes are involved in its metabolism). This process has been studied best for cytochrome P-450 1A2 (CYP1A2), an enzyme that metabolizes caffeine and theophylline (Lambert et al., 1983, 1986; Le Guennec and Billon, 1987). The enzyme activity decreases from childhood levels at earlier pubertal stages in girls than in boys (and, thus, at an earlier age, because girls begin undergoing pubertal stages at younger ages than boys). Once adolescents have reached Tanner stage 4 (of the five stages of sexual maturity identified by Tanner [1962]), drug metabolism and clearance closely resemble adult values.

Recent studies have resulted in changes in a number of recommendations or warnings about the use (or nonuse) of specific medications by children (Meadows, 2003). These changes emphasize the importance of pharmacokinetic studies of drugs that are expected to be beneficial for children of various ages.



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