Maturation of Afmu Excretion in Infants

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

doi:10.1111/j.1472-8206.1989.tb00461.x

Cited by 21 publications

(10 citation statements)

References 11 publications

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“…In children the ratio of acetylated to nonacetylated metabolite is low in newborns through 2 months of age (12% of adult ratio), but then rises to 65% of the adult ratio during the 2-to 6-month interval (Pariente-Khayat et al 1991). This agrees with data showing that most newborns are slow acetylators but that beyond 100 days, the underlying genetic polymorphism (fast vs. slow) becomes evident (Pons et al 1989;Szorady et al 1987). Such data with caffeine are examples of the information that can be obtained from pharmacokinetic data for therapeutic agents.…”

Section: Phase Ii: Data Analysis and Development Of Risk Assessment Asupporting

confidence: 88%

Incorporating children's toxicokinetics into a risk framework.

Ginsberg

Slikker

Bruckner

et al. 2004

Environ Health Perspect

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Children's responses to environmental toxicants will be affected by the way in which their systems absorb, distribute, metabolize, and excrete chemicals. These toxicokinetic factors vary during development, from in utero where maternal and placental processes play a large role, to the neonate in which emerging metabolism and clearance pathways are key determinants. Toxicokinetic differences between neonates and adults lead to the potential for internal dosimetry differences and increased or decreased risk, depending on the mechanisms for toxicity and clearance of a given chemical. This article raises a number of questions that need to be addressed when conducting a toxicokinetic analysis of in utero or childhood exposures. These questions are organized into a proposed framework for conducting the assessment that involves problem formulation (identification of early life stage toxicokinetic factors and chemical-specific factors that may raise questions/concerns for children); data analysis (development of analytic approach, construction of child/adult or child/animal dosimetry comparisons); and risk characterization (evaluation of how children's toxicokinetic analysis can be used to decrease uncertainties in the risk assessment). The proposed approach provides a range of analytical options, from qualitative to quantitative, for assessing children's dosimetry. Further, it provides background information on a variety of toxicokinetic factors that can vary as a function of developmental stage. For example, the ontology of metabolizing systems is described via reference to pediatric studies involving therapeutic drugs and evidence from in vitro enzyme studies. This type of resource information is intended to help the assessor begin to address the issues raised in this paper.

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Section: Phase Ii: Data Analysis and Development Of Risk Assessment Asupporting

confidence: 88%

Incorporating children's toxicokinetics into a risk framework.

Ginsberg

Slikker

Bruckner

et al. 2004

Environ Health Perspect

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“…It has been shown that one of the commonly measured tests concerning the processes of the biotransformation of drugs that undergo acetylation (i.e., acetylation phenotyping) cannot be reliably determined before at least 12 to 15 months of age due to the ongoing maturation of the metabolic systems involved. 21,22 As a result of the intraindividual variations and the long half-life of caffeine in premature infants, monitoring plasma steady-state concentrations of the drug is recommended both to ensure adequate therapeutic levels and to prevent toxic effects of a level that is above the normal range. 23 For a number of years, prior to the establishment of a more economical enzyme immunoassay-based caffeine test by the special chemistry section of the main hospital laboratory, the routine monitoring of caffeine levels in premature infants with apnea at the King Faisal Specialist Hospital and Research Centre (KFSH& RC) was performed by HPLC in the Pharmacokinetics and Therapeutic Drug Monitoring Section of the Research Centre.…”

confidence: 99%

Caffeine Metabolism in Premature Infants

Al‐Alaiyan

Al‐Rawithi

Raines

et al. 2001

The Journal of Clinical Pharma

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Caffeine has been used frequently in the treatment and prevention of apnea of prematurity. The metabolism of caffeine depends on the activities of the hepatic enzymes that vary from one infant to another. The objective of this study was to determine the influence of postnatal age (PNA), birth weight (BW), study weight (SW), gestational age (GA), postconceptual age (PCA), and gender on the maturation of caffeine metabolism in premature infants. The caffeine base was administered orally as a loading dose of 10 mg/kg, followed by a maintenance dose of 2 mg/kg every 24 hours. The steady-state concentration of caffeine and metabolites was measured in plasma taken on the 5th-day postloading dose. The molar concentration ratios for the N3 (N3-), N7 (N7-), N1 (N1-), and all methyl (Nall-) demethylation processes; clearance (CL); and the percentage of molar concentration of caffeine found in plasma to that of the total caffeine and metabolites (%CAF) were calculated from samples collected from 80 neonatal infants. The 48 male and 32 female premature infants had median (range) BW (g), GA (weeks), SW (g), PCA (weeks), and PNA (days) of 1300 (650-2260), 30 (24-34), 1630 (980-2670), 34 (29-40), and 28 (5-60), respectively. The median (range) of the ratios for the %CAF, CL, and the N3-, N7-, N1-, and Nall- were 86.9 (52.9-99.0), 0.127 (0.046-0.503) ml.kg-1.min-1, 0.032 (0-0.438), 0.070 (0.007-0.471), 0.026 (0-0.283), and 0.0463 (0.003-0.303), respectively. When the patients were stratified into four PNA age groups, each older group showed a consistently higher level of caffeine metabolic activity for the N3-, N7-, and Nall- pathways with a corresponding decrease in the %CAF, whereas no significant differences were seen for the N1-pathway or for CL. No pattern of significant differences between the demethylation process ratios, %CAF, or CL was seen between groups of infants when they were stratified according to BW, SW, PCA, or GA. The female infants were found to have significantly higher rates of caffeine metabolism as shown by %CAF, N1-, N3-, and Nall- processes but not the N7-. Multivariate linear regression analysis by two methods demonstrated that PNA is significantly related to %CAF and Nall-, whereas the female patients had higher levels of metabolic activity for the %CAF and N1- process. The authors conclude that the N7-demethy-lation process is the predominate caffeine metabolic process in premature infants. Furthermore, the maturation of the caffeine metabolism in premature infants with a PNA of less than 60 days increases with postnatal age, regardless of birth weight, gestational age, postconceptual age, and study weight. The female neonatal patients demonstrated a higher rate of caffeine metabolism than the males.

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“…Caffeine metabolism occurs in the liver, mainly by CYP1A2, with a subsequent N-demethylation at positions 1, 3 and 7 and hydroxylation at position 8. In preterm neonates, ∼86% of caffeine citrate is excreted unchanged in the urine [97], as the processes of caffeine metabolism maturates progressively through time (N7-demethylation at the post-natal age of ∼4 months [98], acetylation by N-acetyltransferase (NAT2) completely developed by 1 year of postnatal age [99] and 8-hydroxylation activity starting as early as 1 month of age [100]). Thus, the maturity of the hepatic enzymes, dependent mainly by the postnatal age regardless of birthweight and gestational age, affects the plasma half-life of the drug [98,101].…”

Section: Caffeine Pharmacokineticsmentioning

confidence: 99%

“…Elimination of caffeine occurs mainly by renal excretion in the first weeks of life, which is slower in premature and term neonates compared with older children and adults, because of immaturity of renal functions [96]. Clearance of caffeine in neonates is influenced by gestational age, postconceptional age, parenteral nutrition and comorbidities [96,99,100,103,104], with values ranging from 0.08 to 0.13 mL•kg −1 •min −1 compared to that of adults and older children of 1.5 and 4.4 mL•kg −1 •min −1 , respectively [100,105].…”

Section: Caffeine Pharmacokineticsmentioning

confidence: 99%

Caffeine in preterm infants: where are we in 2020?

et al. 2020

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The incidence of preterm birth is increasing, leading to a growing population with potential long-term pulmonary complications. Apnoea of prematurity (AOP) is one of the major challenges when treating preterm infants; it can lead to respiratory failure and the need for mechanical ventilation. Ventilating preterm infants can be associated with severe negative pulmonary and extrapulmonary outcomes, such as bronchopulmonary dysplasia (BPD), severe neurological impairment and death. Therefore, international guidelines favour non-invasive respiratory support. Strategies to improve the success rate of non-invasive ventilation in preterm infants include pharmacological treatment of AOP. Among the different pharmacological options, caffeine citrate is the current drug of choice. Caffeine is effective in reducing AOP and mechanical ventilation and enhances extubation success; it decreases the risk of BPD; and is associated with improved cognitive outcome at 2 years of age, and pulmonary function up to 11 years of age. The commonly prescribed dose (20 mg·kg−1 loading dose, 5–10 mg·kg−1 per day maintenance dose) is considered safe and effective. However, to date there is no commonly agreed standardised protocol on the optimal dosing and timing of caffeine therapy. Furthermore, despite the wide pharmacological safety profile of caffeine, the role of therapeutic drug monitoring in caffeine-treated preterm infants is still debated. This state-of-the-art review summarises the current knowledge of caffeine therapy in preterm infants and highlights some of the unresolved questions of AOP. We speculate that with increased understanding of caffeine and its metabolism, a more refined respiratory management of preterm infants is feasible, leading to an overall improvement in patient outcome.

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Maturation of Afmu Excretion in Infants

Cited by 21 publications

References 11 publications

Incorporating children's toxicokinetics into a risk framework.

Incorporating children's toxicokinetics into a risk framework.

Caffeine Metabolism in Premature Infants

Caffeine in preterm infants: where are we in 2020?

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