Oral and IP caffeine pharmacokinetics under a chronic food-limitation condition

For food-limited rats, serum caffeine was proportional to IP caffeine doses (10-40 mg/kg) for Cmax and area under the curve [AUC(0-24 h)], whereas the three dimethylxanthine (DMX) metabolites of caffeine were disproportional over the dose range. Steady-state concentrations of caffeine and the three metabolites were evident at the 11th day of chronic, daily caffeine IP 20 mg/kg doses. Both caffeine and the three metabolites were dose proportional for Cmax and AUC(0-24 h) by schedule-induced oral caffeine self-administration within the dose range taken (9-38 mg/kg). These results contrast with the nonlinear kinetics of caffeine reported for rats under ad lib conditions. Elimination rate constants (Kel) remained the same for the two routes, but apparent volume of distribution (AVd) and clearance (Cl) were different. The order of the Kel values was caffeine > paraxanthine > theophylline > theobromine. The effects of linear vs. nonlinear caffeine pharmacokinetics may have distinct implications for the resulting pharmacodynamics.