title: In vivo glucuronidation activity of drugs in neonates: extensive interindividual variability despite their young age.
abstract: Compared with phase I isoenzymes, data on isoenzyme-specific phenotypic activity of uridine diphosphate glucuronosyltransferase (UGT) and its covariates in neonates are limited. In vivo observations on morphine, paracetamol (acetaminophen), and propofol disposition throughout childhood confirm the overall low-glucuronidation activity in neonates observed in in vitro studies. In addition to the phenotypic low-glucuronidation activity, in vivo observations of bilirubin (UGT1A1), morphine (UGT2B7), paracetamol (UGT1A6), and propofol (UGT1A9) glucuronidation in neonates display extensive interindividual variability, only in part explained by postmenstrual and postnatal age. Covariates like disease state characteristics (decreased morphine metabolism during therapeutic head cooling), genetic polymorphisms (UGT1A1 genetic variants and differences in bilirubin metabolism), or environmental factors (increased urinary excretion of paracetamol-glucuronide by repeated administration of paracetamol) further contribute to this variability. A focused approach to unveil covariates of the interindividual range is needed to improve our knowledge on drug disposition in early life.
authors.affiliation: Neonatal Intensive Care Unit, University Hospitals Leuven, Belgium. karel.allegaert@uz.kuleuven.ac.be
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.forename: Sophie
authors.initials: S
authors.lastname: Vanhaesebrouck
authors.forename: Rene
authors.initials: R
authors.lastname: Verbesselt
authors.forename: John N
authors.initials: JN
authors.lastname: van den Anker
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D000367:Age Factors; D001663:Bilirubin / Q000494:pharmacology*; D020719:Glucuronides / Q000737:chemistry*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D009020:Morphine / Q000493:pharmacokinetics; D011110:Polymorphism, Genetic; D015742:Propofol / Q000493:pharmacokinetics; D000099148:UGT1A1 Enzyme
chemical_list: D000082:Acetaminophen; D001663:Bilirubin; D020719:Glucuronides; D014453:Glucuronosyltransferase; D009020:Morphine; D015742:Propofol; D000099148:UGT1A1 Enzyme; C037386:acetaminophen glucuronide