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.