title: Developmental changes rather than repeated administration drive paracetamol glucuronidation in neonates and infants.
abstract: OBJECTIVE
  Based on recovered metabolite ratios in urine, it has been concluded that paracetamol glucuronidation may be up-regulated upon multiple dosing. This study investigates paracetamol clearance in neonates and infants after single and multiple dosing using a population modelling approach.
  
  
  METHODS
  A population pharmacokinetic model was developed in NONMEM VI, based on paracetamol plasma concentrations from 54 preterm and term neonates and infants, and on paracetamol, paracetamol-glucuronide and paracetamol-sulphate amounts in urine from 22 of these patients. Patients received either a single intravenous propacetamol dose or up to 12 repeated doses.
  
  
  RESULTS
  Paracetamol and metabolite disposition was best described with one-compartment models. The formation clearance of paracetamol-sulphate was 1.46 mL/min/kg(1.4), which was about 5.5 times higher than the formation clearance of the glucuronide of 0.266 mL/min/kg. The renal excretion rate constants of both metabolites was estimated to be 11.4 times higher than the excretion rate constant of unchanged paracetamol, yielding values of 0.580 mL/min/kg. Developmental changes were best described by bodyweight in linear relationships on the distribution volumes, the formation of paracetamol-glucuronide and the unchanged excretion of paracetamol, and in an exponential relationship on the formation of paracetamol-sulphate. There was no evidence for up-regulation or other time-varying changes in any of the model parameters. Simulations with this model illustrate how paracetamol-glucuronide recovery in urine increases over time due to the slower formation of this metabolite and in the absence of up-regulation.
  
  
  CONCLUSIONS
  Developmental changes, described by bodyweight-based functions, rather than up-regulation, explain developmental changes in paracetamol disposition in neonates and infants.
authors.affiliation: Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden, The Netherlands.
authors.forename: Elke H J
authors.initials: EH
authors.lastname: Krekels
authors.forename: Saskia
authors.initials: S
authors.lastname: van Ham
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.forename: Jan
authors.initials: J
authors.lastname: de Hoon
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D001835:Body Weight; D002657:Child Development; D003198:Computer Simulation; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D015854:Up-Regulation
chemical_list: D000082:Acetaminophen; C037386:acetaminophen glucuronide; C045667:acetaminophen sulfate ester