Caffeine metabolism in premature infants

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 thi s study was to determine the influence of postnatal age (PNA), birth weight (BW) study weight (SW), gestational age (GA), postconceptual age (PCA), an d gender on the maturation of caffeine metabolism in premature infants. The caffeine base was administered orally as a loading dose of 10 mg/kg, follo wed by a maintenance dose of 2 mg/kg every 24 hours. The steady-state conce ntration of caffeine and metabolites was measured in plasma taken on the 5t h-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 plasm a to that of the total caffeine and metabolites (%CAF) were calculated from samples collected from 80 neonatal infants. The 48 male and 32 female prem ature 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), an d 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 (0.046-0.50 3) ml . kg(-1). min(-1), 0.032 (0-0.438), 0.070 (0.007-0.471), 0.026 (0-0.2 8), and 0.0463 (0.003-0.303), respectively. When the patients were stratifi ed into four PNA age groups, each older group showed a consistently higher level of caffeine metabolic activity for the N3-, N7-, and N1-pathways with a corresponding decrease in the %CAF whereas no significant differences we re seen for the N1 - pathway or for CL. No pattern of significant differenc es between the demethylation process ratios, %CAF: or CL was seen between g roups of infants when th ey were stratified according to BW, SW PCA, or GA. The female infants were found to have significantly higher rates of caffei ne metabolism as shown by %CAF: N1-, N3-, and Nall- processes but not the N 7-. Multivariate linear regression analysis by two methods demonstrated tha t PNA is significantly related to % CAF and Nall-, whereas the female patie nts had higher levels of metabolic activity for the %CAF and N1- process. T he authors conclude that the N7-demethy-lation process is the predominate c affeine 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 de monstrated a higher rate of caffeine metabolism than the males.