Purpose: To develop a semi-mechanistic population pharmacokinetic model based on gastric emptying function for acetaminophen plasma concentration in critically ill patients tolerant and intolerant to enteral nutrition before and after prokinetic therapy. Methods: Acetaminophen plasma concentrations were available from a study with 10 tolerant and 20 intolerant patients before and after prokinetic therapy with either erythromycin or metoclopramide. Population pharmacokinetic modelling was carried out in a nonlinear mixed effects analysis software, NONMEM. Results: A four-compartment semi-mechanistic model for stomach, intestine, central and peripheral compartments was described. The rate of emptying of the stomach was described by a first-order rate parameter. The final model has two gastric emptying rate constant parameters: kg1 (1.30 h -1, RSE = 53.84%, T1/2 = 0.53 h) for the intolerant group before prokinetic therapy and kg2 (27.8 h-1, RSE = 59.35%, T1/2 = 0.025 h) for both the intolerant group after prokinetic therapy and the tolerant group. Other parameters and estimates (RSE) in the model were ka = 5.12 h-1 (28.13%), CL = 13.0 L/h (19.62%), CLD = 22.6 L/h (19.78%), V1 = 63.8 L (12.79%) and V2 = 69 L (38.70%). Conclusions: The four-compartment semi-mechanistic population pharmacokinetic model adequately described the data. The gastric emptying half-time is improved by a factor of about 20 in the patients that are intolerant to enteral nutrition after treatment with prokinetic agents. © 2010 Springer Science+Business Media, LLC.