Abstract
Indomethacin (I) undergoes both microsomal oxidation to desmethyl-indomethacin (DMI) and cytosolic deacylation to desbenzoylchloro-indomethacin (DBI). The in vitro postnatal development of these two pathways was examined in the rabbit liver using collagenase-isolated hepatocytes and liver fractions incubated with 0.5 mM 14C-I and appropriate cofactors for drug metabolism activity. Samples were removed at 5 to 15 min intervals for analysis of I metabolites. Deacylation of I to DBI in the 10,000g liver homogenate increased rapidly during the 1st 2 wks after births and demonstrated adult values within day 12 of postnatal age. Results from freshly isolated hepatocytes were very similar to the 10,000g liver homogenate in the pattern of postnatal development of the DBI pathway. Oxidative demethylation of I to DMI in the 10,000g homogenate and isolated cells demonstrated a significant increase only after day 14 of postnatal age and demonstrated only 83% of adult value by day 32 of postnatal age. The isolated microsomal fraction demonstrated a significant postnatal increase in DMI formation during the first 2 wks of postnatal life and reached adult values within day 32 of postnatal age. It is postulated that the difference in postnatal development of I metabolism to DMI between isolated microsomes and the 10,000g homogenate or the isolated hepatocyte is due to endogenous substrates which are competitive for oxidative drug metabolism.
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Evans, M., Bhat, R., Papazafiratou, C. et al. 324 ROLE OF ENDOGENOUS FACTORS IN POST-NATAL DEVELOPMENT OF HEPATIC MICROSOMAL OXIDATIVE METABOLISM IN THE RABBIT. Pediatr Res 15 (Suppl 4), 494 (1981). https://doi.org/10.1203/00006450-198104001-00335
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DOI: https://doi.org/10.1203/00006450-198104001-00335