title: Urinary metabolites to assess in vivo ontogeny of hepatic drug metabolism in early neonatal life.
abstract: In addition to size-dependent allometric metabolic activity, most isoenzymes display age-dependent isoenzyme-specific ontogeny. We therefore need probe drugs to describe isoenzyme-specific ontogeny to develop more sophisticated, physiologically based models. We illustrate the feasibility and the relevance of in vivo assessment of hepatic metabolism, based on observations on urinary elimination of paracetamol and tramadol metabolites in neonates. On the basis of the observations on tramadol disposition, we were able to document that O-demethylation phenotypic activity developed sooner when compared with N-demethylation. During repeated administration of intravenous paracetamol, it was documented that, in addition to postmenstrual and postnatal age (PNA), repeated administration also contributed to the urinary excretion of glucuronidated paracetamol. In both probe drugs evaluated, age only in part explained the interindividual variability observed. Urine metabolites to assess in vivo metabolism of drugs routinely administered in neonates likely increase both the feasibility and clinical relevance of studies on in vivo isoenzyme-specific ontogeny in neonates.
authors.affiliation: Neonatal Intensive Care Unit, University Hospital, Gasthuisberg, Leuven, Belgium. karel.allegaert@uz.kuleuven.ac.be
authors.forename: K
authors.initials: K
authors.lastname: Allegaert
authors.forename: R
authors.initials: R
authors.lastname: Verbesselt
authors.forename: M
authors.initials: M
authors.lastname: Rayyan
authors.forename: A
authors.initials: A
authors.lastname: Debeer
authors.forename: J
authors.initials: J
authors.lastname: de Hoon
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000652:urine; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000652:urine*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000652:urine*; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003640:Dealkylation; D005240:Feasibility Studies; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D015203:Reproducibility of Results; D013379:Substrate Specificity; D014147:Tramadol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000652:urine*
chemical_list: D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; C080580:O-demethyltramadol; D000082:Acetaminophen; D014147:Tramadol; C063776:propacetamol; C080579:N-demethyltramadol; C037386:acetaminophen glucuronide; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase