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Phenytoin metabolism in infants following intravenous and oral administration
Insights
Infants metabolize phenytoin faster than adults, leading to lower blood concentrations despite higher doses. This increased metabolic clearance explains the observed differences in phenytoin disposition between infants and adults.
Area of Science:
- Pharmacokinetics
- Neonatal Medicine
- Drug Metabolism
Background:
- Phenytoin is a widely used anti-epileptic drug.
- Understanding phenytoin disposition in neonates is crucial for safe and effective dosing.
- Previous studies have focused on adult phenytoin pharmacokinetics, with limited data in infants.
Purpose of the Study:
- To investigate the disposition of phenytoin in a cohort of infant patients.
- To compare phenytoin pharmacokinetics in infants with previously established adult data.
- To identify factors contributing to observed differences in phenytoin serum concentrations between infants and adults.
Main Methods:
- Analysis of phenytoin and its metabolites in blood, urine, and feces using gas chromatography/mass spectrometry.
- Administration of multiple intravenous and/or oral doses of phenytoin as part of medical care.
- Comparison of infant data with identical studies previously conducted in adults.
Main Results:
- Infants received a mean phenytoin dose of 8.1 mg/kg/day, resulting in a mean serum concentration of 4.8 µg/ml.
- Adults received a mean dose of 5.3 mg/kg/day, with a mean serum concentration of 12.0 µg/ml.
- No significant differences were observed in the pattern of urinary metabolites or total drug/metabolite recovery between infants and adults, suggesting complete oral absorption in infants.
Conclusions:
- Phenytoin metabolism pathways are conserved between infants and adults.
- Poor oral absorption does not explain the lower phenytoin blood concentrations in infants.
- Higher metabolic clearance of phenytoin in infants accounts for the age-related differences in drug disposition.
Abstract:
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.