title: Effect of diet on the development of drug metabolism by cytochrome P-450 enzymes in healthy infants.
abstract: Orally administered caffeine and dextromethorphan (DM) were used as pharmacologic probes to determine the effect of infant diet on acquisition of cytochrome P-450 (CYP) enzyme activity during the first 6 mo of life. The caffeine elimination rate constant (ke) was determined from serum, and concentrations of caffeine, DM, and their respective metabolites were measured in urine by high-performance liquid chromatography (HPLC). Caffeine ke was low at 2 wk and displayed a significant positive linear correlation with age (p < 0.001); increasing faster in formula-fed than in breast-fed infants (p < 0.001). This occurred concomitantly with a significant increase in urinary 1,7-dimethylxanthine (17X) and 1-methylxanthine (1X) (p < 0.001), suggesting faster acquisition of CYP1A2 activity in formula-fed infants. The urinary molar ratio of (17X + 1X)/caffeine and age strongly predicted caffeine ke (r2 = 0.65; p < 0.001) irrespective of feeding type. CYP3A4 activity, assessed as the molar ratio of 3-hydroxymorphinan/dextrorphan showed a similar marked increase with postnatal age (p < 0.001) that was also greater in formula-fed than in breast-fed infants. Formula feeding appears to accelerate maturation of caffeine and DM metabolism by increasing the activity of CYP1A2 and CYP3A4, respectively. Dietary modification of CYP activity may modulate drug biotransformation and thus alter systemic exposure to xenobiotics from a very early age.
authors.affiliation: Department of Pediatrics, University of Missouri-Kansas City, School of Medicine and the Division of Pediatric Pharmacology and Medical Toxicology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri 64108, USA. mjblake@cmh.edu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blake
authors.forename: Susan M
authors.initials: SM
authors.lastname: Abdel-Rahman
authors.forename: Robin E
authors.initials: RE
authors.lastname: Pearce
authors.forename: J Steven
authors.initials: JS
authors.lastname: Leeder
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Kearns
mesh_terms: D000284:Administration, Oral; D001711:Biotransformation; D001942:Breast Feeding; D002110:Caffeine / Q000008:administration & dosage / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D003915:Dextromethorphan / Q000008:administration & dosage / Q000378:metabolism*; D004790:Enzyme Induction / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D041943:Infant Formula / Q000494:pharmacology*; D007231:Infant, Newborn / Q000378:metabolism*; D008297:Male
chemical_list: D002110:Caffeine; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human