The Impact of Proximal Roux-en-Y Gastric Bypass Surgery on Acetaminophen Absorption and Metabolism

Background: Roux-en-Y gastric bypass (RYGBS), a surgery that creates a smaller stomach pouch and reduces the length of small intestine, is one of the most common medical interventions for the treatment of obesity.

Aim: The aim of this study was to determine how RYGBS affects the absorption and metabolism of acetaminophen.

Materials and methods: Ten morbidly obese patients received 1.5 g of liquid acetaminophen (APAP) orally on three separate pharmacokinetic study days (i.e., pre-RYGBS baseline and 3 and 12 months post-RYGBS). Plasma was collected at pre-specified timepoints over 24 hours, and the samples were analyzed using liquid chromatography-mass spectrometry for APAP, APAPglucuronide (APAP-gluc), APAP-sulfate (APAP-sulf), APAP-cysteine (APAP-cys), and APAP-Nacetylcysteine (APAP-nac).

Result: Following RYGBS, peak APAP concentrations at the 3-month and 12-month visits increased by 2.0-fold compared to baseline (p=0.0039 and p=0.0078, respectively) and the median time to peak concentration decreased from 35 to 10 minutes. In contrast, peak concentrations of APAP-gluc, APAP-sulf, APAP-cys, and APAP-nac were unchanged following RYGBS. The apparent oral clearance of APAP and the ratios of metabolite area under the curve (AUC)-to-APAP AUC for all four metabolites decreased at 3 and 12 months post-RYGBS compared to the presurgical baseline. In a simulation of expected steady-state plasma concentrations following multiple dosing of 650 mg APAP every 4 hours, post-RYGBS patients had higher steady-state peak APAP concentrations compared to healthy individuals and obese pre-RYGBS patients, though APAP exposure was unchanged compared to healthy individuals.

Conclusion: Following RYGBS, the rate and extent of APAP absorption increased and decreased formation of APAP metabolites was observed, possibly due to downregulation of Phase II and cytochrome P450 2E1 enzymes.