title: O-demethylation of tramadol in the first months of life.
abstract: OBJECTIVE
  Assess in vivo O-demethylation activity in the first months of life.
  
  
  METHODS
  Time-concentration profiles of tramadol (M) and O-demethyl tramadol (M1) in plasma and urine were simultaneously collected in the first 24 h of continuous intravenous tramadol administration in neonates and young infants. M and M1 were determined by high performance liquid chromatography. Correlations between perinatal characteristics [postnatal age (PNA), postmenstrual age (PMA)] and the contribution of metabolites (M, M1) to overall tramadol elimination and to the plasma and urine log M/M1 were calculated.
  
  
  RESULTS
  Plasma samples were available in 20/29 and complete 24-h urine collections were available in 25/29 neonates (25-53 weeks PMA). Mean plasma log M/M1 value (>4 h, n=86) was 0.8 (SD 0.4). A significant correlation between plasma log M/M1 and PMA (r=-0.73, P<0.0001) and PNA (r=-0.58, P<0.005) was observed. In a multiple regression model, only PMA remained an independent variable. Mean urine log M/M1 was 0.94 (SD 0.7). Significant correlations of the urine log M/M1 ratio with PMA (r=-0.73, P<0.0001) and PNA (r=-0.56, P=0.0035) were observed. In a multiple regression model with the urine log M/M1 ratio as dependent variable, only PMA remained an independent variable. The maturational half-life of the log M/M1 ratio in early neonatal life in the age range evaluated is about 12-16 weeks without plateau.
  
  
  CONCLUSIONS
  O-demethylation activity was already observed in early neonatal life. A significant correlation with PMA was documented, but PMA can only partially explain the observed variability in O-demethylation activity. Polymorphism therefore likely already contributes to the interindividual variability observed in neonates.
authors.affiliation: Neonatal Intensive Care Unit, Department of Paediatrics, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. karel.allegaert@uz.kuleuven.ac.be
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.forename: J N
authors.initials: JN
authors.lastname: Van den Anker
authors.forename: R
authors.initials: R
authors.lastname: Verbesselt
authors.forename: J
authors.initials: J
authors.lastname: de Hoon
authors.forename: C
authors.initials: C
authors.lastname: Vanhole
authors.forename: D
authors.initials: D
authors.lastname: Tibboel
authors.forename: H
authors.initials: H
authors.lastname: Devlieger
mesh_terms: D000375:Aging / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016014:Linear Models; D009294:Narcotics / Q000097:blood / Q000378:metabolism* / Q000652:urine; D014147:Tramadol / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000652:urine
chemical_list: D009294:Narcotics; C080580:O-demethyltramadol; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6