Article Text

AGE AND POLYMORPHISMS, NOT DISEASE CHARACTERISTICS, CONTRIBUTE TO O- AND N-DEMETHYLATION VARIABILITY OF TRAMADOL IN NEONATES
  1. K Allegaert1,
  2. J VandenAnker2,
  3. S Vanhaesebrouck1,
  4. R Verbesselt3,
  5. V Cossey1,
  6. C Vanhole1,
  7. J deHoon3
  1. 1Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium
  2. 2Division of Pediatric Clinical Pharmacology, Children’s National Medical Center, Washington, DC, USA
  3. 3Center for Clinical Pharmacology, University Hospitals Leuven, Leuven, Belgium

Abstract

Objective To investigate determinants of interindividual variability of O- and N-demethylation of tramadol in neonates.

Methods Tramadol (M), O-demethyl tramadol (M1), N-demethyl tramadol (M2) concentrations, log M/M1 and log M/M2 were assessed in 24 hour urine collections during tramadol administration.1 Correlations with postnatal age (PNA), postmenstrual age (PMA), disease characteristics (cardiopathy, (cardiac) surgery, small-for gestational age (SGA)) and CYP2D6 activity score were investigated.

Results Observations were available in 67 neonates. Log M/M1 was 1.01 (0.63). Inverse relationships between log M/M1 and PMA (−0.69), PNA (−0.39) and CYP2D6 activity score (−0.52) were observed. Log M/M1 values in early neonatal life (<day 8) were higher compared to late neonatal life (day 8–28) (p<0.01). In a multiple forward regression, PMA and the CYP2D6 activity remained independent variables of the log M/M1. The mean log M/M2 was 1.71 (0.46). Inverse relationships between log M/M2 and PMA (−0.35) and PNA (−0.4) were observed. Log M/M2 values in early neonatal life were higher compared to late neonatal life (p<0.01). In a multiple forward regression model, PMA and PNA remained independent variables of the log M/M2.

Conclusions Important interindividual variability in O and N-demethylation activity of tramadol was observed. O-demethylation was in part explained by PMA and CYP2D6 activity score, N-demethylation was in part explained by age. Disease characteristics did not contribute to the explained variability in drug metabolism in neonates.

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