Maturation of Caffeine N-Demethylation in Infancy: A Study Using the 13CO2 Breath Test

Abstract

ABSTRACT. Four premature neonates and eight infants 1-19 months old received caffeine for apnea. The usual morning oral dose was substituted by 1,3,7 I3C-trimethylxanthine (13C-tri CAF) as the citrate salt. Five breath samples were collected the day before (day 1) and the day of 13C-tri CAF administration (day 2). Plasma (after each breath collection) and urine were collected on day 2. 13C-C02 exhalation was determined by isotope ratio mass spectrometry. Caffeine and its metabolites were measured using high-pressure liquid chromatography. Assessment of the labeled C 0 2 in the breath revealed no detectable I3C-tri CAF N-demethylation activity in infants before 45 wk postconceptional age. However, demethylation (as urinary metabolites) has been detected before that age. Two-, 4-, and 6-h cumulative excretion of 13C-tri CAF as 13C-C02 increased with postnatal age and correlated with caffeine plasma clearance (r = 0.840, p c 0.01). These results were consistent with those obtained for urinary metabolites. In one infant (19 months old) the cumulative excretion of I3C-C02 while crying was 65% of the value observed during quiet breathing. The measurement of caffeine demethylation using the caffeine C 0 2 breath test is feasible in infants and is a safe and noninvasive method to determine age related changes in P450I-dependent N-demethylase activity. (Pediatr Res 23: 632-636, 1988)

Biotransformation of caffeine in human liver microsomes from foetuses, neonates, infants and adults.

“…This discrepancy may be attributable to the relatively higher weight of the liver in infants than in adults, the in vitro data being expressed with regard to the specific activity of enzyme-containing preparations while in vivo data also take the total amount of liver tissue into account. No influence of maturation on N-1-demethylation was detected in the 0-300 days age range, while the production of theobromine was higher in adults than in children suggesting that, as shown in vivo, maturation of N-i -demethylation appears to be delayed compared with N-3 and N-7-demethylation [8,10]. No influence of maturation was found in vitro on C-8-hydroxylation while in vivo data suggest that maturational changes occur within the first 19 months of life [10].…”

“…However, the maturation of N-3 and N-7-demethylation occurs over at least a 0-300 day age range, while the in vivo data suggested that these demethylations reach maturity at around 120 days of age [8,10]. This discrepancy may be attributable to the relatively higher weight of the liver in infants than in adults, the in vitro data being expressed with regard to the specific activity of enzyme-containing preparations while in vivo data also take the total amount of liver tissue into account.…”

“…Developmental changes metabolites are formed. These are paraxanthine in caffeine elimination and metabolism have been (1-7X), theophylline (1-3X), theobromine (3-7X) and described in 0 to 19 month old children [8][9][10]. The 1-3-7-trimethyluric acid (1-3-7U), obtained from N-3-, profiles of the maturational changes observed in vivo vary according to the metabolic pathway, suggesting that they may depend on different cytochromes P450.…”

Inhibition of caffeine metabolism by ciprofloxacin in children with cystic fibrosis as measured by the caffeine breath test.

“…Subsequent treatment with growth hormone decreased the 3-N-demethylation of caffeine. Other studies using urinary caffeine metabolite ratios [13] and the caffeine breath test [14], have shown that 3-N-demethylation of caffeine is low in infants under the age of 6 months. Therefore, studies of drug interactions on CYP1A2 activity should exclude infants in whom the enzyme is not fully developed, i.e.…”

“…Six children (aged 4-15 years) were studied both before and 10 days after commencing a 14 The subjects remained seated for 10 min prior to the collection of the first breath sample. They then remained seated throughout the whole test and were kept occupied by the Research Nurse in order to minimise physical activity which can affect carbon dioxide production and result in dilution of the labelled carbon dioxide [6].…”