Abstract
Background: Major changes in drug clearance are observed during infancy, at least partially based on ontogenic regulation of metabolic pathways but data on maturation of UDP-glucuronosyltransferase (UGT)-activity in term and especially in preterm neonates are still limited. Since paracetamol provides a good substrate to study ontogeny of UGT-1A6 activity, urinary metabolites of propacetamol were determined in neonates in whom repeated administration of propacetamol (a prodrug of paracetamol for intravenous use) was part of their routine clinical care.
Methods: Following informed parental consent, urine samples were collected during consecutive time intervals in neonates who received consecutive administrations of propacetamol. In these urine samples, paracetamol-glucuronide, paracetamol-sulfate and free paracetamol were determined using High Performance Liquid Chromatography. Spearman rank and linear multiple regression (MedCalc®) were used to study correlations of postnatal age, of postmenstrual age and of repeated administration on the relative contribution of paracetamol-glucuronide to overall urine paracetamol elimination (G/T ratio).
Results: 142 samples were collected in 18 neonates with a median postnatal age of 19 days (range 1–173) and a median postmenstrual age of 39 weeks (range 29–60). Median urine G/T ratio was 14 % (range 1–53). Besides increasing G/T ratio with increasing postnatal (p<0.0001) and postmenstrual age (p<0.01), repeated administration (p<0.01) also correlated with an increasing G/T ratio and this observation remained significant (p<0.01) when these 3 perinatal variables were entered in a multiple linear regression model.
Conclusions: The range of urine G/T ratio's documented in this study reflects the major variability in the ontogeny of UGT-activity in neonates of various postnatal and postmenstrual ages. Besides the significant effect of postnatal and postmenstrual age on UGT-activity, an additional independent significant effect of repeated administration of propacetamol was documented. Therefore, observed variability in paracetamol clearance can not only be explained by postnatal and postmenstrual age, but also in part by the number of administered doses of this drug, reflecting an inductive effect of paracetamol on UGT-activity.
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Allegaert, K., Tibboel, D., Devlieger, H. et al. 7 Ontogeny of Udp-Glucuronosyltransferase Activity During Repeated Administration of Propacetamol in Neonates. Pediatr Res 56, 465 (2004). https://doi.org/10.1203/00006450-200409000-00030
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DOI: https://doi.org/10.1203/00006450-200409000-00030
