tent with in vitro data (Cresteil, 1998), functional CYP1A2 activity is among the last of the P450 activities to be acquired by the newborn and appears to be further delayed in breast-fed infants (Le Guennec and Billon, 1987).

The ontogeny of CYP2D6 activity has not been well characterized to this point in time. Investigators have initiated a study designed to test the hypothesis that within the first year of life acquisition of CYP2D6 activity consistent with genotype is dependent upon both gestational age and postconceptional age. Dextromethorphan phenotyping (administration of 0.3 mg of dextromethorphan DM as Robitussin® Pediatric per kg of body weight after the last evening feed techniques) is conducted with infants during the first year of life at six points timed to coincide with well-baby visits to a primary care physician. Overnight urine recovered from diapers is analyzed by high-pressure liquid chromatography for levels of dextromethorphan and three metabolites. Although the data are preliminary and have not yet been subjected to peer review, data to date for 45 samples obtained 13.9 ± 2.9 (mean ± standard deviations) days after birth indicate that at this postnatal age, the CYP2D6 phenotype (ratio of dextromethorphan to dextrorphan in urine) is consistent with the corresponding genotype determined as described above. However, changes in the pattern of dextromethorphan metabolite excretion in urine suggest that maturation of CYP3A (possibly intestinal CYP3A) is delayed relative to that of hepatic CYP2D6, occurring over the first 4 months of life.

In summary, available information concerning the developmental regulation of individual CYP isoforms is inferred from pharmacokinetic studies of drugs considered to be model substrates for those particular CYP isoforms. In most cases, the data consist of serial measurements of the parent compound from which clearance is estimated and compared with values obtained for adults. Concurrent data for metabolites would be extremely valuable since the ability to characterize individual drug biotransformation pathways becomes more likely. Longitudinal phenotyping studies with healthy children and specific disease populations may help bridge the gap between preclinical in vitro drug biotransformation studies. Subsequent pharmacokinetic studies. These studies may provide important information concerning the effects of disease processes on drug disposition. Ultimately, the goal of developmental pharmacogenetic studies is to better understand the determinants of interindividual variability during childhood such that pharmacotherapeutics can truly be optimized for children of all ages.



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