Abstract
Summary: Metabolism of indomethacin was examined in freshly isolated hepatocytes prepared by liver collagenase perfusion of fetal (28) and neonatal rabbits of 3, 5, 10, 12, and 25 days of age. Initial cell viability was more than 90% and linear rates of metabolism were observed for up to 2 hr of incubation. Deacylation of indomethacin to desbenzoyl indomethacin showed a rapid increase early in postnatal development while microsomal O-demethylation to desmethyl indomethacin was increased significantly only in the hepatocytes from 25-day-old rabbits. Glucuronide conjugates of indomethacin and indomethacin metabolites accounted for less than 8% of the total metabolites in hepatocytes from 25-day-old rabbits and less than 2% in the 3− to 5-day-old rabbits. The maturational development of indomethacin in metabolism may account for previously reported gestational dependent half-life of the drug in the premature infant (9). However, the factors that regulate development of indomethacin metabolism appear to be under more than one control system.
Speculation: The noted adverse effects from indomethacin in the premature infant suffering from patent ductus arteriosus probably results from drug accumulation. Several independent pathways of metabolism for indomethacin have been demonstrated and the differences in their postnatal maturation may cause considerable variation in the patient disposition of the drug. These variations are important in the consideration of drug therapy in the premature infant.
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Evans, M., Papazafiratou, C., Bhat, R. et al. Indomethacin Metabolism in Isolated Neonatal and Fetal Rabbit Hepatocytes. Pediatr Res 15, 1406–1410 (1981). https://doi.org/10.1203/00006450-198111000-00003
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DOI: https://doi.org/10.1203/00006450-198111000-00003