Pharmacokinetics of paraxanthine, one of the primary metabolites of caffeine, in the rat.

The pharmacokinetic of paraxanthine, one of the primary metabolites of caffeine, is described for the first time. Groups of adult male rats were given different doses of paraxanthine as iv bolus injections. Blood cell/plasma partition and the binding of the compound to rat plasma proteins (determined by equilibrium dialysis) were investigated. The fraction bound (15%) remained constant in the concentration range of 1-100 micrograms/ml. Partition was also constant over a wide range of doses. Up to the 10 mg/kg dose, the paraxanthine followed first order kinetics and blood concentrations vs. time data were described by a one-compartment, open model system. The mean half-life and elimination rate constant were 1 hr and 0.70 hr-1, respectively. The average apparent volume of distribution was 1.50 liters/kg and total clearance was 0.90 liter/hr/kg. After larger doses (15 and 30 mg/kg), kinetics were nonlinear. The area under the blood concentration-time curve increased, but not in proportion to the dose, and modifications of pharmacokinetic parameters were shown. These findings indicate that in the rat paraxanthine is eliminated by a saturable process with an apparent Km of about 31 micrograms/ml and an apparent Vmax of about 0.40 micrograms/ml/min. Close estimates were obtained by two different methods of calculation. Our results suggest that the pharmacokinetic profile of paraxanthine could be important to understand the kinetics and the potential toxic effects of its parent compound, caffeine, in animals and man.