Effects of nutritional status on acetaminophen measurement and exposure

Introduction: Fasting, as well as a high-fat diet, might increase the risk on acetaminophen-induced toxicity after an acute overdose. Therefore, it has been suggested to lower the threshold for acetylcysteine treatment to prevent liver injury in case of fasting. This study aims to investigate the effects of 36 hours of fasting and three days of a hypercaloric high-fat diet on acetaminophen measurement and exposure. Methods: Nine healthy male subjects were enrolled in a randomized crossover intervention study. Subjects received 1000mg oral acetaminophen after an overnight fast following: (1) regular diet,(2) 36h of fasting and (3) three days of a hypercaloric high-fat diet consisting of 500ml of cream (1715 kcal) supplemented to their regular diet. Pharmacokinetic parameters were determined by non-compartmental analysis. Samples were analyzed by an enzymatic colorimetric method used in routine practice and by LC-MS/MS being the gold standard. Agreement between these methods was assessed by the Bland-Altman method. Results: Short-term fasting increased acetaminophen exposure by 20% (Delta AUC0-8 hours, p = .04) in comparison with the control diet. Three days of hypercaloric high-fat diet did not affect acetaminophen exposure (Delta AUC(0-8) hours= 9%, p = .67). The intraclass correlation coefficient between the enzymatic assay and LC-MS/MS methods of the fasting samples was 0.46 (0.28-0.61), compared to 0.87 (0.81-0.92) and 0.87 (0.79-0.91) in the control and high-fat samples respectively. Conclusions: Short-term fasting increases acetaminophen exposure in healthy subjects, whereas no effect is observed after a high-fat diet. Furthermore, short-term fasting decreases the accuracy of the enzymatic colorimetric method when measuring relatively low acetaminophen concentrations. This suggests considering nutritional status when assessing the risk of acetaminophen-induced toxicity, although further research at toxic doses is needed.