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 Kmand Vmaxcould be estimated for six subjects who took all four doses. Considerable interindividual variability in these parameters and particularly Kmswas found. The Kmfor overall elimination averaged 133 umol/L (range 55-213 ujnol/L) and the Vmax611 µmol/h (2,640 mg/day; range 452-813 µmol/h). With regard to individual metabolic routes, the Kmfor theophylline metabolism to 1-MU was 88 ± 41 (mean ± SD) µmol/L and the Vmaxwas 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 Kmfor metabolism to DMU was 179 ± 92 u.mol/L and the Vmaxwas 357 ±122 u, mol/h. The Kmvalues 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 Kms, 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.
- Nonlinear kinetics