Ontogeny of dextromethorphan O- and N-demethylation in the first year of life.
The exponential increase in the number of drugs used to treat infant and childhood illnesses necessitates an understanding of the ontogeny of drug biotransformation for the development of safe and effective therapies. Healthy infants received an oral dose (0.3 mg/kg) of dextromethorphan (DM) at 0.5, 1, 2, 4, 6, and 12 months of age. DM and its major metabolites were measured in urine. CYP2D6 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. Genotyping data indicated a strong correlation between CYP2D6 genotype and DM O-demethylation (beta=-0.638; 95% CI: -0.745, -0.532; P<0.001). CYP2D6 activity was detectable and concordant with genotype by 2 weeks of age, showed no relationship with gestational age, and did not change with post natal age up to 1 year. In contrast, DM N-demethylation developed significantly more slowly over the first year of life. Genotype and the temporal acquisition of drug biotransformation are critical determinants of a drug response in infants.
Blake
M J
MJ
Division of Pediatric Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA.
Gaedigk
A
A
Pearce
R E
RE
Bomgaars
L R
LR
Christensen
M L
ML
Stowe
C
C
James
L P
LP
Wilson
J T
JT
Kearns
G L
GL
Leeder
J S
JS
D000375:Aging / Q000378:metabolism*; D000483:Alleles; D000996:Antitussive Agents / Q000493:pharmacokinetics*; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D003640:Dealkylation; D003915:Dextromethorphan / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male
D000996:Antitussive Agents; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6