Abstract
Objective
Assess in vivo O-demethylation activity in the first months of life.
Methods
Time–concentration profiles of tramadol (M) and O-demethyl tramadol (M1) in plasma and urine were simultaneously collected in the first 24 h of continuous intravenous tramadol administration in neonates and young infants. M and M1 were determined by high performance liquid chromatography. Correlations between perinatal characteristics [postnatal age (PNA), postmenstrual age (PMA)] and the contribution of metabolites (M, M1) to overall tramadol elimination and to the plasma and urine log M/M1 were calculated.
Results
Plasma samples were available in 20/29 and complete 24-h urine collections were available in 25/29 neonates (25–53 weeks PMA). Mean plasma log M/M1 value (>4 h, n=86) was 0.8 (SD 0.4). A significant correlation between plasma log M/M1 and PMA (r=−0.73, P<0.0001) and PNA (r=−0.58, P<0.005) was observed. In a multiple regression model, only PMA remained an independent variable. Mean urine log M/M1 was 0.94 (SD 0.7). Significant correlations of the urine log M/M1 ratio with PMA (r=−0.73, P<0.0001) and PNA (r=−0.56, P=0.0035) were observed. In a multiple regression model with the urine log M/M1 ratio as dependent variable, only PMA remained an independent variable. The maturational half-life of the log M/M1 ratio in early neonatal life in the age range evaluated is about 12–16 weeks without plateau.
Conclusions
O-demethylation activity was already observed in early neonatal life. A significant correlation with PMA was documented, but PMA can only partially explain the observed variability in O-demethylation activity. Polymorphism therefore likely already contributes to the interindividual variability observed in neonates.
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Acknowledgements
The clinical research of K. Allegaert is supported by the Fund for Scientific Research, Flanders (Belgium) by a Clinical Doctoral Grant (A6/5–KV–G1). There was no other financial support to perform this study in neonates, besides the above mentioned support from the Fund for Scientific Research Flanders (Belgium).
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Allegaert, K., Van den Anker, J.N., Verbesselt, R. et al. O-demethylation of tramadol in the first months of life. Eur J Clin Pharmacol 61, 837–842 (2005). https://doi.org/10.1007/s00228-005-0045-3
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DOI: https://doi.org/10.1007/s00228-005-0045-3