ALTERATIONS IN THEOPHYLLINE (T) METABOLISM DURING THE FIRST YEAR OF LIFE

Maturational changes in T pharmacokinetics were evaluated in 45 infants; postconceptional age (PCA) 30.9-95.7 wks. After achievement of steady-state on T maintenance therapy, multiple serum and urine samples were obtained over dosing interval and assayed by HPLC for T and metabolites: caffeine (C), 1-methyluric acid (1MU), 3-methylxanthine (3MX), 1,3-dimethyluric acid (1,3MU). Mean(SD) T clearance (Cl) increased significantly (p 50 wks from 21.9(6.3) to 26.6(7.7) and 57.7(17.6). ml/hr/kg, respectively. Concomitant decrease (p 0.10) were found in some infants up to 55 weeks PCA. Stepwise multiple regression analysis showed urinary excretion of 3MX to be the primary parameter explaining the change in both T Cl (r=0.81, p<0.01) and serum C/T ratio (r=0.66, p<0.01). Urinary excretion of 3MX (demethylated) for the 3 PCA groups was 1.4, 4.2 and 13.1% compared to 23%, 41% and 44% for 1.3MU (oxidative). Disappearance of serum C and maturation of T metabolism is dependent on development of demethylation pathway which does not occur until approximately 55 wks PCA. Prior to that age, serum C concentration should be monitored in patients receiving T.