Nonlinear renal excretion of theophylline and its metabolites, 1-methyluric acid and 1,3-dimethyluric acid, in rats.

Plasma pharmacokinetics and renal excretion of theophylline (TP) and its metabolites were investigated in rats. Plasma concentrations of TP declined in a monoexponential manner, while those of 1-methyluric (MU) and 1,3-dimethyluric (DMU) declined in a biexponential manner upon respective i.v. bolus injection of each compound at 6 mg/kg dose. The total body clearances (CLt) of the metabolites were 4-6 fold larger than that of TP, while the distribution volumes of them at steady-state (Vdss) were 40-50% smaller than that of TP. The metabolites showed their plasma peaks in 30 min after i.v. injection of TP indicating very rapid metabolism of TP. Metabolism of TP to DMU was more than fourfold faster than that to MU. Renal excretion of TP and its metabolites was studied in urine flow rate (UFR)-controlled rats. The renal clearance (CLr) of TP was inversely related to plasma TP concentrations, and much smaller than the glomerular filtration rate (GFR) suggesting tubular secretion and profound reabsorption in the renal tubule. The CLr of each metabolite also showed that inverse relationship, but far exceeded GFR suggesting that tubular secretion plays a major role in their elimination. The CLr of the metabolites were reduced to less than GFR by i.p. injection of probenecid (142.7 mg/kg). It supports that the metabolites are secreted in the renal tubule, and suggests that they share a common transport system in their secretion processes with probenecid. On the other hand, the CLr of TP was not affected significantly by the probenecid treatment. Considering the inverse relationship of TP between the CLr and its plasma concentrations, no effect of probenecid on CLr of TP is most likely due to negligible contribution of the secretion to the overall CLr of TP.