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Maturation of caffeine N-demethylation in infancy: a study using the 13CO2 breath test
1Département de Pharmacologie Périnatale et Pédiatrique, Hôpital Saint-Vincent de Paul, Université René Descartes, Paris, France.
Insights
The caffeine CO2 breath test is a safe, noninvasive method to measure caffeine N-demethylation in infants. This test reveals age-related changes in P4501-dependent N-demethylase activity, crucial for understanding drug metabolism in neonates and infants.
Area of Science:
- Pharmacology
- Neonatology
- Pediatric Gastroenterology
Background:
- Caffeine is commonly used to treat apnea in premature neonates and infants.
- Assessing caffeine metabolism is vital for optimizing therapeutic use and understanding drug interactions in this population.
- Previous methods for assessing caffeine metabolism in infants were invasive or less sensitive.
Purpose of the Study:
- To evaluate the feasibility, safety, and noninvasiveness of a novel 13C-labeled caffeine (13C-tri CAF) CO2 breath test.
- To assess age-related changes in caffeine N-demethylation activity in infants using this breath test.
- To correlate breath test results with plasma caffeine clearance and urinary metabolite excretion.
Main Methods:
- Four premature neonates and eight infants (1-19 months) received an oral dose of 13C-tri CAF.
- Breath samples were collected pre- and post-dose for 13C-CO2 analysis via isotope ratio mass spectrometry.
- Plasma and urine samples were collected to measure caffeine and its metabolites using high-pressure liquid chromatography.
Main Results:
- The 13C-tri CAF CO2 breath test detected no N-demethylation activity before 45 weeks postconceptional age, aligning with urinary metabolite data.
- Cumulative 13C-CO2 excretion increased with postnatal age and significantly correlated with plasma caffeine clearance (r=0.840, p<0.01).
- In one infant, crying reduced 13C-CO2 excretion by 65%, indicating potential physiological influences.
Conclusions:
- The 13C-tri CAF CO2 breath test is a feasible, safe, and noninvasive method for assessing caffeine demethylation in infants.
- This breath test allows for the determination of age-related changes in P4501-dependent N-demethylase activity.
- The findings support the use of this breath test to study drug metabolism and its developmental changes in pediatric populations.
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 13C-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-CO2 exhalation was determined by isotope ratio mass spectrometry. Caffeine and its metabolites were measured using high-pressure liquid chromatography. Assessment of the labeled CO2 in the breath revealed no detectable 13C-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-CO2 increased with postnatal age and correlated with caffeine plasma clearance (r = 0.840, p less than 0.01). These results were consistent with those obtained for urinary metabolites. In one infant (19 months old) the cumulative excretion of 13C-CO2 while crying was 65% of the value observed during quiet breathing. The measurement of caffeine demethylation using the caffeine CO2 breath test is feasible in infants and is a safe and noninvasive method to determine age related changes in P4501-dependent N-demethylase activity.