title: Maturational changes in the in vivo activity of CYP3A4 in the first months of life.
abstract: OBJECTIVE
  To document maturational changes of the in vivo activity of CYP3A4 in the first months of life.
  
  
  METHODS
  The contribution of tramadol (M), O-demethyl tramadol (M1, CYP2D6-mediated) and N-demethyl tramadol (M2, CYP3A4-mediated) to the overall elimination of tramadol and the log M/M2 was assessed in 24-hour urine collections during continuous intravenous tramadol administration. Correlations with perinatal characteristics (postnatal age (PNA) and postmenstrual age (PMA)) were studied.
  
  
  RESULTS
  Of the total amount of tramadol administered in a 24-hour interval to 25 neonates and young infants (PMA 25 - 53 weeks), 34.5% (SD 6.1) were retrieved in the urine as parent compound or metabolite in a 24-hour interval. This retrieved material consisted primarily of tramadol 79% (SD 18), M1 10% (SD 17) and M2 3% (SD 3.4). The contribution of M (r2 = -0.53), M1 (r2 = 0.46) and M2 (r2 = 0.16) to overall M elimination correlated with increasing PMA. The mean log M/M2 was 1.44 (SD 0.46) and there was an inverse correlation between the log M/M2 ratio and PMA (r2 = -0.43, 95% CI for r = -0.84 to -0.34, p = 0.0006) and PNA (r2 = -0.25, 95% CI for r = -0.78 to -0.16, p = 0.008). The maturational half-life of the log M/M2 ratio was 16 - 20 weeks. In a multiple regression model, PMA was the only significant variable accounting for the interindividual variability in log M/M2.
  
  
  CONCLUSIONS
  PMA was found to be the most important maturational change determing the in vivo activity of CYP3A4. The activity of CYP3A4 is relatively delayed in the first months of life compared to the developmental changes in CYP2D6 activity described earlier, however, the overall weak correlations reflect that PMA explains only in part the interindividual variability observed.
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: J N
authors.initials: JN
authors.lastname: Van den Anker
authors.forename: A
authors.initials: A
authors.lastname: Debeer
authors.forename: V
authors.initials: V
authors.lastname: Cossey
authors.forename: R
authors.initials: R
authors.lastname: Verbesselt
authors.forename: D
authors.initials: D
authors.lastname: Tibboel
authors.forename: H
authors.initials: H
authors.lastname: Devlieger
authors.forename: J
authors.initials: J
authors.lastname: de Hoon
mesh_terms: D000367:Age Factors; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D016014:Linear Models; D014147:Tramadol / Q000031:analogs & derivatives / Q000378:metabolism / Q000652:urine
chemical_list: C080580:O-demethyltramadol; D014147:Tramadol; C080579:N-demethyltramadol; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human