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Ontogeny of dextromethorphan O- and N-demethylation in the first year of life

M J Blake1, A Gaedigk, R E Pearce

  • 1Division of Pediatric Pharmacology and Medical Toxicology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA.

Clinical Pharmacology and Therapeutics
|February 16, 2007
PubMed

Insights

Infant drug metabolism, specifically dextromethorphan (DM) O-demethylation via CYP2D6, is predictable by genotype from 2 weeks old. N-demethylation matures more slowly in the first year of life.

Area of Science:

  • Pharmacology
  • Pediatrics
  • Genetics

Background:

  • Infant drug metabolism is complex and crucial for developing safe therapies.
  • Understanding drug biotransformation ontogeny is essential due to the increasing number of medications for children.

Purpose of the Study:

  • To investigate the developmental trajectory of dextromethorphan (DM) biotransformation in infants.
  • To correlate CYP2D6 genotype with DM O-demethylation and N-demethylation in early life.

Main Methods:

  • Healthy infants received oral dextromethorphan (DM) doses at various ages (0.5 to 12 months).
  • Urine samples were analyzed for DM and its metabolites.
  • CYP2D6 genotype was determined using polymerase chain reaction-restriction fragment length polymorphism.

Main Results:

  • CYP2D6 genotype strongly correlated with DM O-demethylation (P<0.001).
  • CYP2D6 activity was detectable and genotype-concordant by 2 weeks of age, independent of gestational or postnatal age up to 1 year.
  • DM N-demethylation developed significantly slower during the first year of life.

Conclusions:

  • CYP2D6 genotype is a critical determinant of DM O-demethylation in infants from early life.
  • The maturation of DM N-demethylation is a slower process in the first year.
  • Both genetic factors and the developmental timing of drug biotransformation influence infant drug responses.

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