This study presents a circulatory model of glucose kinetics for application to non-steady-state conditions, examines its ability to predict glucose appearance rates from a simulated oral glucose load, and compares its performance with compartmental models. A glucose tracer bolus was injected intravenously in rats to determine parameters of the circulatory and two-compartment models. A simulated oral glucose tolerance test was performed in another group of rats by infusing intravenously labeled glucose at variable rates. A primed continuous intravenous infusion of a second tracer was given to determine glucose clearance. The circulatory model gave the best estimate of glucose appearance, closely followed by the two-compartment model and a modified Steele one-compartment model with a larger total glucose volume. The standard one-compartment model provided the worst estimate. The average relative errors on the rate of glucose appearance were: circulatory, 10%; two-compartment, 13%; modified one-compartment, 11%; standard one-compartment, 16%. Recovery of the infused glucose dose was 93+/-2, 94+/-2, 92+/-2 and 85+/-2%, respectively. These results show that the circulatory model is an appropriate model for assessing glucose turnover during an oral glucose load.