Non-linear elimination processes of theophylline.

After intravenous and oral administration of theophylline to four healthy subjects, the plasma concentration-time curve of theophylline could be described by linear pharmacokinetics, although total clearance in all subjects decreased when the dose was increased; the doses were theophylline 193.2 mg and 386.4 mg i.v. and 161 mg and 322 mg p.o. Total clearance was 65.5 +/- 11.3 ml/min. Renal clearance changed from 15.2 +/- 9.5 ml/min in the first two hours after administration to 4.9 +/- 5.5 ml/min between 16 and 24 h (p less than 0.001). 1,3-dimethyluric acid (DMU), the major metabolite of theophylline, was determined in urine and in plasma. The renal clearance of DMU was constant at 496.7 +/- 180 ml/min. There was some evidence that at high plasma concentrations of theophylline the formation of DMU might be a zero-order process. The renal excretion rate of 1-methyluric acid (1-MU) paralleled that of DMU, which is in accordance with the assumption that DMU is demethylated to 1-MU. 3-methylxanthine (3-MX) was excreted in urine at a constant rate over 10 h, the rate being equivalent to the dose, which is contrary to the assumption of Michaelis-Menten-kinetics. 3-methyluric acid was found to be a minor metabolite of theophylline and 1-methylxanthine (1-MX) could not be detected. The cumulative amounts excreted in urine, expressed as a percentage of the dose and corrected for molecular weight, were theophylline 16.6 +/- 6.5%, DMU 44.3 +/- 7.0%, 1-MU 24.3 +/- 4.8%, 3-MX 12.9 +/- 3.4% and 3-MU 2.2 +/- 1.8%.