Caffeine Metabolism in Premature Infants

Abstract

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.

Correlation between Serum Caffeine Levels and Changes in Cytokine Profile in a Cohort of Preterm Infants

“…Some of this variability could be related to the collection times, because daily variability is reported to be between 6.1% to 35.0%. 30,39 However, because the peak caffeine level is at 30 to 120 minutes, the half-life is approximately 100 hours and the dosing is every 24 hours, the differences between levels within the 12 hours before the next dose are expected to be minimal by 1 week of treatment. 15,30 In our cohort, two factors appeared to be positively associated with higher caffeine levels (≥16 μ g/mL after 1 week of treatment): older GA and Caucasian race.…”

Caffeine citrate – Is it a silver bullet in neonatology?

“…15 The rate of metabolism of caffeine is found to be higher in female than male preterm neonates. 16 Peak plasma concentration with both oral and intravenous route is almost the same and is reached within thirty minutes to two hours. The clearance increases non-linearly with increasing post-natal age, reaching a plateau at 120 days, and volume of distribution increases linearly with increasing weight.…”

Quantification of uric acid, xanthine and hypoxanthine in human serum by HPLC for pharmacodynamic studies

“…Multiple serum lots were spiked with UA/X/HX at 500/10/10 M, respectively, for the test. Because of the structural similarity of X and HX to caffeine (1,3,7-trimethyl X), three major metabolites of caffeine from hydroxylation, oxidative demethylation by cytochrome P-450 1A2 and xanthine oxidase metabolism [45][46][47] were tested for possible chromatographic interference on the HPLC system. The results showed that 1-methyl-X at 30 M (approximately 30-fold the expected serum concentration) contributed as a small interference peak at the retention time of X as depicted in the overlaid chromatograms of X and 1-methyl-X in Fig.…”