O-demethylation of tramadol in the first months of life.
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.
Allegaert
Karel
K
Neonatal Intensive Care Unit, Department of Paediatrics, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. karel.allegaert@uz.kuleuven.ac.be
Van den Anker
J N
JN
Verbesselt
R
R
de Hoon
J
J
Vanhole
C
C
Tibboel
D
D
Devlieger
H
H
D000375:Aging / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016014:Linear Models; D009294:Narcotics / Q000097:blood / Q000378:metabolism* / Q000652:urine; D014147:Tramadol / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000652:urine
D009294:Narcotics; C080580:O-demethyltramadol; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6