Nonlinear metabolic disposition of theophylline

Eleven healthy volunteers were given maintenance treatment with oral theophylline in increasing doses (210-1,260 mg/day). Seven subjects took four different doses, three subjects took three doses and one subject discontinued treatment after only two doses. Plasma and urine were collected during a dose interval at steady state. Theophylline in plasma and urine and metabolites in urine (1-methyluric acid, 1-MU; 3-methylxanthine, 3-MX; 1,3-di-methyluric acid, DMU) were determined by high-performance liquid chromatography. Total clearance of theophylline as well as clearances to all three metabolic products (but not theophylline renal clearance) decreased with increasing dose. The individual Michaelis-Menten parameters K_mand V_maxcould be estimated for six subjects who took all four doses. Considerable interindividual variability in these parameters and particularly K_mswas found. The K_mfor overall elimination averaged 133 umol/L (range 55-213 ujnol/L) and the V_max611 µmol/h (2,640 mg/day; range 452-813 µmol/h). With regard to individual metabolic routes, the K_mfor theophylline metabolism to 1-MU was 88 ± 41 (mean ± SD) µmol/L and the V_maxwas 110 ± 15 µmol/h; the Km for metabolism to 3-MX was 90 ± 37 (jimol/L and the ymax was 78 ± 13 µmol/h; the K_mfor metabolism to DMU was 179 ± 92 u.mol/L and the V_maxwas 357 ±122 u, mol/h. The K_mvalues for the iV-demetnylation pathways (1-MU and 3-MX) were significantly correlated (r = 0.95; p < 0.01). It is concluded that nonlinear metabolic disposition of theophylline occurs, particularly by the two iV-demethylation pathways, within recommended ranges of maintenance doses and steady-state concentrations, and that the interindividual variability in Michaelis-Menten parameters, particularly K_ms, is great. The clinical implication of these findings is that large changes in maintenance dose of theophylline should be performed with caution and be accompanied by plasma concentration monitoring.