Affiliations: Neonatal Intensive Care Unit, Division of Woman and
Child, University Hospitals Leuven, Leuven, Belgium | Division of Pediatric Clinical Pharmacology,
Children's National Medical Center, Washington, DC, USA | Departments of Pediatrics, Pharmacology and
Physiology, George Washington University School of Medicine and Health
Sciences, Washington, DC, USA | Center for Clinical Pharmacology, University Hospitals
Leuven, Leuven, Belgium
Note: [] Corresponding author: Karel Allegaert, MD, PhD, Neonatal
Intensive Care Unit, Division of Woman and Child, University Hospitals, campus
Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Tel.: +32 16 343210; Fax:
+32 16 343209; E-mail: [email protected]
Abstract: Objective: To investigate the impact of disease characteristics on
the interindividual variability of O- and N-demethylation 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.
