Intra- and interindividual variability of glucuronidation of paracetamol during repeated administration of propacetamol in neonates

Background: Major changes in drug clearance and metabolism are observed during infancy, in part based on ontogenic regulation of various metabolic pathways. Since paracetamol provides a good substrate to study UGT (1A6) activity, urinary metabolites of propacetamol were determined in neonates in whom propacetamol was repeatedly administered. Methods: Paracetamol glucuronide (APAP-G), paracetamol sulphate (APAP-S) and free paracetamol were determined in urine samples of neonates during repeated administration of propacetamol. Spearman rank and linear multiple regression (MedCalc®, Mariakerke, Belgium) were used to study the effect of postnatal age, of postconceptional age and of repeated administration on the relative contribution of APAP-G to overall urine paracetamol (APAP-G + APAP-S + free paracetamol) elimination (G/T ratio). Results: 147 samples were collected in 23 neonates. Molar median G/T ratio was 14% (range 1-53). Besides increasing G/T ratio with increasing postnatal (p<0.0001) and postconceptional age (p<0.01), repeated administration (p<0.01) also correlated with an increasing G/T ratio, and repeated administration remained significant (p<0.01) after correction of postnatal and postconceptional age in a multiple regression model. Conclusion: Major variability in the ontogeny of UGT activity to overall elimination of paracetamol was documented in neonates. Besides postnatal and postconceptional age, a significant effect of repeated administration on UGT activity was documented.

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