Although the pharmacokinetics of acetylsalicylic acid (ASA) absorption and metabolism in therapeutic doses are well described, there is little information for overdose. A porcine model was developed to study ASA pharmacokinetics in overdose and to establish the feasibility of using area-under-the-curve (AUC) for serum ASA vs time rather than salicylate vs time as an indirect method of quantifying total drug absorption. Such a model could be useful in comparing the effectiveness of different methods of gastrointestinal decontamination in poisoning. The hydrolysis of ASA to salicylate, known to be a first-order process in therapeutic doses, was confirmed to remain first-order at high serum concentrations using iv aspirin in 2 pigs. Five simulated overdoses were then carried out in 4 pigs using 500 mg ASA/kg administered enterally as intact tablets. Serial determinations of both serum ASA and salicylate concentration were carried out over 72 h. Plots of ASA concentration vs time for each of the trials revealed delayed, multiple and erratic peaks consistent with a bolus effect from sudden dissolution of aspirin concretions, suggesting our model accurately simulates human overdose. Despite the variable peaks, the AUC of ASA concentration vs time for the 5 trials revealed a coefficient of variation of only 13%, compared with 27% for salicylate concentration vs time AUC. This suggests that serial measurements of serum ASA in a porcine ASA overdose model can be used to measure total drug absorption and thereby compare the effectiveness of different methods of gastrointestinal decontamination.