title: Intra- and interindividual variability of glucuronidation of paracetamol during repeated administration of propacetamol in neonates.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neonatal Intensive Care Unit, Department of Paediatrics, University Hospital, Gasthuisberg, Leuven, Belgium. karel.allegaert@uz.kuleuven.ac.be
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.forename: Jan
authors.initials: J
authors.lastname: de Hoon
authors.forename: Rene
authors.initials: R
authors.lastname: Verbesselt
authors.forename: Christine
authors.initials: C
authors.lastname: Vanhole
authors.forename: Hugo
authors.initials: H
authors.lastname: Devlieger
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D000367:Age Factors; D000700:Analgesics / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000652:urine; D001835:Body Weight; D002851:Chromatography, High Pressure Liquid; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D016014:Linear Models; D008657:Metabolic Clearance Rate; D015999:Multivariate Analysis; D014554:Urination
chemical_list: D000700:Analgesics; D000082:Acetaminophen; C063776:propacetamol; C037386:acetaminophen glucuronide; C045667:acetaminophen sulfate ester