Ontogenic development

Developmental changes in UGT activity have been extensively studied both in vivo and in vitro using morphine as a substrate. Morphine glucuronidation to both morphine-6-glucuronide and morphine-3-glucuronide is mediated mainly by UGT2B7.107 Morphine was found to undergo significant glucuronidation by the fetus liver. In vitro studies in hepatic microsomes obtained from fetuses (15-27 weeks) indicated that the glucuronidation rates were 10-20% of that observed in adult microsomes.108 In addition, the mean rate of morphine glucuronidation in fetal livers obtained after hysterectomy was twofold higher than that obtained from induced abortion livers, suggesting a possible regulatory mechanism for UGTactivity related to the birth process (Table 4).25 The glucuronidation of morphine in vivo has also been demonstrated in premature neonates as young as 24 weeks of gestation. Studies with other substrates which are mainly or partially glucuronidated by UGT2B7, such as naloxone, an opiate agonist, benzodiazepines, and nonsteroidal antiinflammatory drugs are all suggestive of a reduced glucuronidation ability in neonates compared to adults.109

The developmental regulation of UGT enzymes was also demonstrated with acetaminophen, which is glucuronidated mainly by UGT1A6 and to some extent by UGT1A9.110 Acetaminophen glucuronide formation is undetectable in the fetus; low levels are seen after birth and only reach adult levels of glucuronidation after 10 years of age.111 This lack of UGT activity is compensated, however, by the high activity of sulfotransferases in infants and young children.112

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