Acetaminophen protein adduct concentrations during therapeutic dosing in patients with class II-III obesity compared to non-obese and overweight patients: a prospective observational gender stratified cohort study

Background: Obese patients may need higher doses of acetaminophen (APAP) for adequate analgesia, due to increased total clearance and distribution volume. APAP-induced hepatotoxicity is mainly caused through CYP2E1 pathway. Its activity is induced by obesity, potentially endangering the safety profile of APAP. Metabolic-dysfunction associated liver disease (MASLD) is an important associated risk factor for APAP induced-hepatotoxicity. Objectives: This pilot study aimed at observing and analyzing CYP2E1 related protein adducts (APAP-cysteine and APAP-mercapturate) in obese compared to non-obese patients during therapeutic dosing of APAP. Study design and setting: Interim analysis of an ongoing prospective observational gender-stratified cohort PK study, conducted at Ghent University Hospital. Methods: 35 obese (BMI>35kg/m²) and 18 non-obese (18,5kg/m²<BMI< 30kg/m²) patients undergoing laparoscopy were included. All patients received intravenously 2g APAP and 1g q6h. Plasma concentrations of protein adducts were measured at predefined timepoints after first and fifth dose. Main outcome measures: CYP2E1 activity was indirectly assessed by measuring APAP protein adducts. Linear mixed model analysis was used to assess correlations between the repeated measurements of protein adducts plasma concentrations and: obesity, age, gender, total body weight, lean body mass and metabolic syndrome. Hepatotoxicity was evaluated by assessing liver function markers and observing the 1.0 µmol/L threshold for APAP protein adducts. Results: No statistically significant interaction was observed between obesity and the measurements for APAP- cysteine or APAP-mercapturate. No significant interaction was noted between metabolic syndrome and these adducts. Significant correlations were found for APAP-Cysteine with sex, total body weight, and lean body mass. Statistically significant differences in bilirubin, prothrombin time (PT), and international normalized ratio (INR) were found in obese patients at 30 hours, though without clinical relevance. Conclusions: Obesity and metabolic syndrome did not have a significant impact on CYP2E1 activity. Liver function markers were significantly different in obese patients, without clinical relevance.