In vivo and perfused liver caffeine kinetics in the rat.

The kinetics of caffeine (1,3,7-TMX) was investigated in male rats given four different doses (1, 2.5, 10 and 25 mg/kg), comparing the patterns found in vivo and after liver perfusion. The same animals were used in both experimental conditions in order to reduce the variability of the caffeine profile. For doses less than 10 mg/kg or mg/L, caffeine blood or perfusate concentrations/time profiles followed first-order kinetics and the elimination rate constant (average 0.013 min-1) and half-life (55 min) were similar for the in vivo and ex vivo conditions. After larger doses (10 and 25 mg/kg or mg/L), kinetics were nonlinear. The area under the blood or medium concentration-time curve increased, but not in proportion to the dose, and modifications of pharmacokinetic parameters were observed, with significant differences for t 1/2 and CL after 10 and 25 mg/kg or mg/L, due to dose-dependent elimination of caffeine at these doses (Km of 8.3 and 7.8 micrograms/ml in vivo and in vitro, respectively). The two different approaches gave close kinetic estimates in vivo and in vitro. Thus, under standardized conditions, the isolated perfused liver technique is a useful tool for studying the kinetics of drugs eliminated by hepatic metabolism.