Nonlinear Metabolic Disposition of Theophylline

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Abstract
Eleven healthy volunteers were given maintenance treatment with oral theophylline, in increasing doses (210-1260 mg/day). Seven subjects took 4 different doses, 3 subjects took 3 doses and 1 subject discontinued treatment after only 2 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-dimethyluric acid, DMU) were determined by high-performance liquid chromatography. Total clearance of theophylline, as well as clearances to all 3 metabolic products (but not theophylline renal clearance), decreased with increasing dose. The individual Michaelis-Menten parameters Km and Vmax could be estimated for 6 subjects who took all 4 doses. Considerable interindividual variability in these parameters, and particularly Km, was found. The Km for overall elimination averaged 133 .mu.mol/l (range 55-213 .mu.mol/l) and the Vmax averaged 611 .mu.mol/h (2640 mg/day; range 452-813 .mu.mol/h). With regard to individual metabolic routes, the Km for theophylline metabolism to 1-MU was 88 .+-. 41 (mean .+-. SD) .mu.mol/l and the Vmax was 110 .+-. 15 .mu.mol/h; the Km for metabolism to 3-MX was 90 .+-. 37 .mu.mol/l and the Vmax was 78 .+-. 13 .mu.mol/h; the Km for metabolism to DMU was 179 .+-. 92 .mu.mol/l and the Vmax was 357 .+-. 122 .mu.mol/h. The Km values for the N-demethylation pathways (1-MU and 3-MX) were significantly correlated (r = 0.95; P < 0.01). Nonlinear metabolic disposition of theophylline occurs, particularly by the 2 N-demethylation pathways, within recommended ranges of maintenance doses and steady-state concentrations. The interindividual variability in Michaelis-Menten parameters, particularly Km, is great. The clinical implication of these findings is that large changes in maintenance doses of theophylline should be performed with caution and should be accompanied by plasma concentration monitoring.