Developmental Changes of Caffeine Elimination in Infancy

Pons, Gérard; Carrier, Odile; Mo, Richard; Rey, Elisabeth; d’Athis, Philippe; Moran, Claude; Badoual, J; Olivé, G

doi:10.1159/000457700

Cited by 51 publications

(28 citation statements)

References 9 publications

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“…We have shown that caffeine metabolism by human liver microsomes undergoes maturational changes, similar to those reported in vivo [8][9][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].…”

Section: Discussionsupporting

confidence: 67%

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

Cazeneuve

Pons

Rey

et al. 1994

Brit J Clinical Pharma

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1 Caffeine metabolism was studied in human liver microsomes from foetuses (n = 10), neonates (n = 10), infants (n = 9) and adults (n = 5). Caffeine and its metabolites, 1-3-7-trimethyluric acid, paraxanthine, theophylline and theobromine, were assayed by h.p.l.c. Methoxyresorufin-O-demethylase activity (MEROD) was determined and immunoquantifiable levels of CYP1A2 were measured.2 The formation of the dimethylxanthines by N-3, N-7 or N-i-demethylation was significantly less in foetuses, neonates and infants than in adults, as shown previously in vivo. The formation of 1-3-7-trimethyluric acid (C-8-hydroxylation) was not significantly different between age groups. The production of total dimethylxanthines, paraxanthine and theophylline increased significantly with age within the neonate-infant group over at least the 0-300 day range (rs = 0.739, 0.667, 0.682, respectively). These data differ from those reported in vivo which suggested that N-3 and N-7-demethylations matured at about 120 days. The difference in maturational profiles of each metabolic pathway suggests that the reactions depend on different isoenzymes. The delay in the maturation of N-1 compared with N-3 and N-7-demethylation is in agreement with previous in vivo data. 3 In the neonate-infant group, only N-3-demethylation correlated with both MEROD activity (rs = 0.681; P < 0.05) and CYP1A2 microsomal concentration (r, = 0.454; P = 0.05), suggesting that, as in adults, this reaction depends on CYP1A2. 4 In the foetal samples, the production of total dimethylxanthines, paraxanthine and theobromine decreased significantly (rs = -0.879, -0.767, -0.708, respectively) with increasing gestational age. Only CYP3A has previously been detected in human foetal liver; neither CYPlAl nor CYP1A2 were present, suggesting that the metabolic pathways of caffeine depend on CYP3A at this stage of development.

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Section: Discussionsupporting

confidence: 67%

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

Cazeneuve

Pons

Rey

et al. 1994

Brit J Clinical Pharma

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“…In the univariate and multiple linear regression analyses (Table 4), the BW was a significant parameter (P=0.024), whereas the GA, postconceptional age, and Apgar score were not significant. The PK parameters determined were clearance (0.033 L/h), the volume of distribution (0.371 L), 11) . In a previous study, the recommended loading dose of caffeine citrate was 20 mg/kg and the maintenance treatment (5 to 10 mg/kg once a day) should be administered orally or by intravenous infusion.…”

Section: Resultsmentioning

confidence: 99%

Clinical Pharmacokinetics of Caffeine in Korean Preterm Infants with Apnea of Prematurity

Lim¹,

Son²,

Shin³

et al. 2017

Neonatal Med

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Purpose: Caffeine shows wide interindividual pharmacokinetic (PK) variation, and therapeutic drug monitoring (TDM) may be needed. The PK profile of caffeine in Korean preterm neonates was investigated, and factors influencing the clearance of caffeine were analyzed. Methods: Fifty-nine preterm neonates receiving caffeine for apnea of prematurity were enrolled in the study (gestational age, 29.5±2.2 weeks and birth weight [BW], 1,318±358 g). Caffeine (20 mg/kg) was intravenously administered to each neonate as a loading dose, followed by a maintenance dose of 5-10 mg/kg/d. A total of 190 serum concentrations were measured for population PK analysis and modeling using nonlinear mixed-effects model (NONMEM ® ) software. Results:The mean serum concentration of caffeine was 15.4±4.5 mg/L (range 7.8-33.0 mg/L). High serum concentrations (>20 mg/L) were noted in 36 samples (29%). At the first measurement of serum caffeine, the mean postmenstrual age was 33.9±2.3 weeks, mean BW was 1,802±471 g, mean duration of treatment was 7.4±9.4 days, and mean sampling time after the last dose was 21.8±2.1 hours. In the population PK analysis, the clearance was 0.033 L/h and volume of distribution was 0.371 L. Typical clearance was calculated as 0.0293×(BW/70) 1.33 . Among the subjects receiving 5 mg/kg/d caffeine, the most significant risk factor associated with high serum concentrations (>20 mg/L) was low BW (P=0.024). Conclusion: BW was the only covariate that influenced caffeine clearance in preterm neonates. Preterm neonates with low BW should be carefully monitored for apnea and adverse reactions in addition to undergoing TDM.

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“…The expired gas was collected over a 1-min period using macokinetic parameters with maturation. Elsewhere we de-a face mask (Rendell Baker size 0 or 1 according to the patient scribed the pattern of this variation (5). The important interin-size) fitted via a small dead volume (4 ml) two-way valve (Ambu dividual variability of CAF kinetic parameters complicates the Paedi, M.M.S.-SANOFI, France) into a 3-liter latex bag.…”

Section: Methodsmentioning

confidence: 99%

“…Blood samples were centrifuged and plasma was kept at +4" C for less than 24 h. Each urine sample was collected separately between two consecutive doses on day 2 and frozen at -20" C. The plasma concentration of CAF and metabolite concentrations in urines were determined using high-performance liquid chromatography as described previously (5,10). Metabolite concentrations in urine were determined on pooled complete consecutive collections.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 1988

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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)

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Developmental Changes of Caffeine Elimination in Infancy

Cited by 51 publications

References 9 publications

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

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

Clinical Pharmacokinetics of Caffeine in Korean Preterm Infants with Apnea of Prematurity

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

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