5 Effect of Diet on the Ontongeny of Drug Biotransformation in Healthy Infants.

Abstract

Drug biotransformation can be altered by diet in adults resulting in drug accumulation and toxicity, or in some cases, enhanced elimination. The cytochrome P450 enzymes (CYPs) are a super family of heme-containing phase I enzymes responsible for biotransformation of a significant number of commonly used pharmacologic agents and a large array of endogenous substrates. Previous studies suggest that drug metabolism by CYPs differs between breast-fed and formula-fed infants. The effect of infant diet on the development of functional CYP activity is assessed in this report. Oral doses of caffeine and dextromethorphan were used as pharmacologic probes to track CYP enzyme activity in neonates seen at 6 visits over their first 6 months of life. The caffeine elimination rate constant (ke) was determined from serum caffeine levels obtained on alternating visits. At all visits, levels of caffeine, dextromethorphan, and their respective metabolites were determined by HPLC in urine samples collected over a 24 hr post-dose period. The serum caffeine ke of infants at their first study visit (2 weeks post-natal age) was unrelated to post-conceptional age. Caffeine elimination was low in infants at this first visit and displayed a significant positive linear correlation with increasing post-natal age (ke = .004 (Age [weeks]) + .001; p<0.001). Caffeine ke increased faster in formula-fed infants (slope = .005 95%CI: 0.004, 0.006) than in breast-fed infants (slope = .002 95%CI: 0.001, 0.002) (p<0.001) concomitant with increased conversion of caffeine to 3-demethylated metabolites. In contrast, breast feeding significantly increased the urinary fractional molar recovery of 3-methylxanthine (fr3X) [(fr3X) = .004 Age [weeks] + .016; p< 0.01] suggesting that this feeding modality produces a relative shunt in metabolism towards 7-demethylated metabolites. Dextromethorphan metabolism, assessed as the fractional molar recovery of 3-hydroxymorphinan (fr3HM), showed a similar marked increase with postnatal age [(fr3HM) = .014 Age [weeks] + .203; p< 0.001] that did not differ between diets. The maturation of caffeine elimination does not appear to begin until after birth. Formula feeding appears to accelerate the development of caffeine metabolism but not dextromethorphan. There may be specific ligand(s) unique to infant formula or human breastmilk that modify the developmental regulation of CYP1A gene expression and/or activity. Dietary modification of CYP activity may alter drug bioavailability and increase exposure to modified xenobiotics or endogenous metabolites from a very early age.