Postmenstrual age and CYP2D6 polymorphisms determine tramadol o-demethylation in critically ill neonates and infants.
To document determinants of O-demethylation in critically ill (pre)term neonates and infants, tramadol (M) and O-demethyl tramadol (M1) concentrations were quantified in eighty-six 24 h urine collections and 168 plasma samples. A significant correlation of urine log M/M1 (0.98, SD 0.66) and plasma log M/M1 (0.78, SD 0.45) with postmenstrual age (PMA) (r = -0.69 and -0.65) was observed. One-way analysis of variance documented a significant decrease in urine log and plasma log M/M1 with increasing CYP2D6 activity score (F value 11.6 and 22.55). PMA and CYP2D6 activity score determined the urine and plasma log M/M1 (R 0.59 and 0.64) in a forward multiple regression model. We therefore conclude that PMA and CYP2D6 polymorphisms determined O-demethylation activity in (pre)term neonates and young infants, illustrating the impact of pharmacogenetics on drug metabolism in neonates although a relevant part of the interindividual varaibility remained unexplained. Besides compound-specific relevance, CYP2D6 iso-enzyme specific data on in vivo ontogeny of O-demethylation can contribute to safer and more effective administration of drugs metabolized by the same route in this population.
Allegaert
Karel
K
Neonatal Intensive Care Unit, University Hospitals, campus Gasthuisberg, B-3000 Leuven, Belgium. karel.allegaert@uz.kuleuven.ac.be
van Schaik
Ron H N
RH
Vermeersch
Steve
S
Verbesselt
Rene
R
Cossey
Veerle
V
Vanhole
Christine
C
van Fessem
Marianne
M
de Hoon
Jan
J
van den Anker
John N
JN
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001711:Biotransformation; D001724:Birth Weight; D016638:Critical Illness; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D003640:Dealkylation; D004334:Drug Administration Schedule; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007262:Infusions, Intravenous; D008954:Models, Biological; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D014147:Tramadol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D000701:Analgesics, Opioid; C080580:O-demethyltramadol; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6