OII-C-1Effect of diet on the ontogeny of caffeine and dextromethorphan metabolism

Abstract

BACKGROUND/AIMS Dietary constituents alter drug metabolism in adults contributing to therapeutic failure or toxicity. The effect of diet on drug disposition in infants was investigated in this study. METHODS Oral caffeine (CAF) and dextromethorphan (DEX) were given to 35 healthy infants at 6 visits over their first 6 months of life. CAF was measured in plasma to determine the apparent elimination rate constant (ke). CAF, DEX, and their metabolites were measured by HPLC in urine samples collected over 24 hr. RESULTS CAF ke at the first visit (2 wks) was low and unrelated to post-conceptional age. After 2 wks, CAF ke displayed a significant positive linear correlation with post-natal age (ke = .004 (Age[wks]) + .001; p<0.001). CAF ke increased faster in formula-fed infants (slope = 0.005 95%CI: 0.004, 0.006) than in breast-fed infants (slope = 0.002 95%CI: 0.001, 0.002) (p<0.001). CAF ke in formula-fed infants was associated with increased conversion of CAF to 3-demethylated metabolites. DEX metabolism, assessed as the fractional molar recovery of 3-hydroxymorphinan (fr3HM), showed a similar marked increase with postnatal age[(fr3HM) = .014 Age[wks] + .203; p< 0.001] that did not differ between diets. CONCLUSIONS Formula feeding accelerates the development of CAF metabolism but not DEX. Components of an infant's diet differentially modify the developmental regulation of drug metabolizing enzymes. Dietary modification of drug metabolism appears to alter exposure to xenobiotics from a very early age. Clinical Pharmacology & Therapeutics (2005) 79, P6–P6; doi: 10.1016/j.clpt.2005.12.018