DRUG METABOLISM IN CHILDREN AND ADOLESCENTS: INSIGHTS FROM THERAPEUTIC ADVENTURES

Presented by Gregory L. Kearns, Pharm. D., FCP

Marion Merrell Dow/Missouri Chair in Pediatric Pharmacology, and Professor of Pediatrics and Pharmacology, University of Missouri, Kansas City, and Chief, Division of Pediatric Clinical Pharmacology and Experimental Therapeutics, Children's Mercy Hospital and Clinics, Kansas City

Over the past two decades, much information concerning drug metabolism in infants, children, and adolescents has been derived as a ''by-product" of pharmacokinetic investigations designed, in part, to determine whether age-dependent differences in drug disposition (e.g., drug clearance) were evident. For many compounds, developmental differences in drug clearance have, for drugs where the primary biotransformation pathways are known, produced partial developmental "road maps" that have provided information on the patterns of ontogeny for important drug-metabolizing enzymes.

The use of pharmacokinetic data to examine the ontogeny of a drug-metabolizing enzyme is well illustrated by theophylline, a pharmacologic substrate for the P450 cytochrome CYP1A2. In 1981, Nassif et al. reported that the elimination half-lives of theophynine ranged between 9 and 18 hours in term infants 6 to 12 weeks of postnatal age. Furthermore, those investigators found a linear relationship between postnatal age and theophylline half-life, with values declining to approximately 3 to 4 hours by 48 weeks of life. Over a decade later, Krans et al. (1993) demonstrated that the dramatic alterations in theophylline plasma clearance occurring between 30 weeks (i.e., approximately 10 ml/h/kg) and 100 weeks (i.e., approximately 80 ml/h/kg) of postconceptional age was primarily the result of age-dependent differences in the metabolism of theophylline by CYP1A2 were dependent pathways. Further characterization of theophylline biotransformation in humans by Tjia et al. (1996) demonstrated that theophylline was adequate for use as a pharmacologic "probe" for the assessment of CYP1A2 activity given that approximately 80 percent of the formation of 1,3-dimethyluric acid at theophylline concentrations of 100 micromolar (µM) was catalyzed by this P450 isoform. Recently, Tateishi et al. (1999) administered theophylline to 51 pediatric patients ranging in age from 1 month to 14 years of age and examined the urinary ratios of three metabolites: 1-methyluric acid, 3-methylxanthine, and 1,3-dimethyluric acid. Examination of the urinary ratio of 1,3-dimethyluric acid to either 3-methylxanthine or 1-methyluric acid (both of which are generated by CYP1A2) demonstrated that CYP1A2 activity as competent as that of adults was reached by 3 months of postnatal age, a finding that corroborated earlier studies of the pharmacokinetics of the drug in infants (Kraus et al., 1993). Although these data collectively appear to have created a well-



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