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-dimethyluric 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 Km and Vmax could be estimated for six subjects who took all four doses. Considerable interindividual variability in these parameters and particularly Km:s was found. The Km for overall elimination averaged 133 mumol/L (range 55-213 mumol/L) and the Vmax 611 mumol/h (2,640 mg/day; range 452-813 mumol/h). With regard to individual metabolic routes, the Km for theophylline metabolism to 1-MU was 88 +/- 41 (mean +/- SD) mumol/L and the Vmax was 110 +/- 15 mumol/h; the Km for metabolism to 3-MX was 90 +/- 37 mumol/L and the Vmax was 78 +/- 13 mumol/h; the Km for metabolism to DMU was 179 +/- 92 mumol/L and the Vmax was 357 +/- 122 mumol/h. The Km values for the N-demethylation pathways (1-MU and 3-MX) were significantly correlated (r = 0.95; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)