Phenytoin metabolism in infants following intravenous and oral administration.

The disposition of phenytoin was examined in 7 infants with a mean age of 22 days and a mean weight of 3,756 g. Multiple doses of phenytoin were administered intravenously and/or orally as a part of required medical care. Gas chromatography/mass spectrometry was employed for analyses of phenytoin and three metabolites - 5-(4-hydroxyphenyl)-5-phenylhydantoin, methylated 3,4-catechol, and 3,4-dihydrodiol - in blood, urine, and feces. Data from identical studies previously conducted in adults were utilized for comparison with the infants. The mean phenytoin dose (+/- SD) in infants was 8.1 +/- 4.4 mg/kg/day, and the mean serum concentration (+/- SD) was 4.8 +/- 4.6 micrograms/ml. In adults, the mean dose was 5.3 +/- 0.6 mg/kg/day, and the mean serum concentration was 12.0 +/- 1.9 micrograms/ml. No significant differences were found between infants and adults in the pattern of urinary metabolites or in the total recovery of phenytoin and metabolites in 24-hour urine samples. These results indicate that pathways for phenytoin metabolism are the same in infants and adults. Absorption of an oral dose of phenytoin in infants appeared to be completely based on recoveries of drug and metabolites in urine and on the fact that less than 3% of an oral dose could be found in stools. The results of these studies indicate that the low blood concentrations of phenytoin resulting from the relatively high daily dosage of phenytoin in infants, when compared to adults, cannot be explained on the basis of poor oral absorption of phenytoin. These age-related differences must be due to a relatively high metabolic clearance of the drug in infants.