The interindividual variability in metabolism of the analgesic tramadol in neonates is independent of their disease state characteristics

Objective: To investigate the impact of disease characteristics on the interindividual variability of O- and Ndemethylation of tramadol in neonates. Methods: Tramadol (M), O-demethyl tramadol (M1), N-demethyl tramadol (M2), log M/M1 and log M/M2 were assessed in 24 hours urine collections during intravenous tramadol. Correlations with postnatal (PNA) and postmenstrual age (PMA), disease state characteristics [cardiopathy, (cardiac) surgery, small-for gestational age (SGA)] and CYP2D6 activity score were investigated. Results: Collections were available in 67 neonates. The mean log M/M1 was 1.01 (SD 0.63). Inverse relationships between log M/M1 and PMA, PNA and CYP2D6 activity score were observed. Median log M/M1 in early life (< day 8) was higher compared to late neonatal life (day 8-28) (p < 0.01). In a multiple forward regression model, PMA and CYP2D6 activity score remained independent variables. The mean log M/M2 was 1.71 (SD 0.46). Inverse relationships between log M/M2 and PMA and PNA were observed. Median log M/M2 in early life was higher compared to late neonatal life (p < 0.01). In a multiple forward regression model, PMA and PNA remained independent variables. Conclusions: Extensive interindividual variability in demethylation metabolic activity was observed. O-demethylation was in part explain by PMA and CYP2D6 activity score, N-demethylation by PMA and PNA while disease characteristics had no impact of demethylation activity.