Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen

Abstract

Introduction: Acetaminophen (paracetamol) is mainly metabolized via glucuronidation and sulphation, while the minor pathway through cytochrome P450 (CYP) 2E1 is held responsible for hepatotoxicity. In obese patients, CYP2E1 activity is reported to be induced, thereby potentially worsening the safety profile of acetaminophen. The aim of this study was to determine the pharmacokinetics of acetaminophen and its metabolites (glucuronide, sulphate, cysteine and mercapturate) in morbidly obese and non-obese patients.

Methods: Twenty morbidly obese patients (with a median total body weight [TBW] of 140.1 kg [range 106-193.1 kg] and body mass index [BMI] of 45.1 kg/m(2) [40-55.2 kg/m(2)]) and eight non-obese patients (with a TBW of 69.4 kg [53.4-91.7] and BMI of 21.8 kg/m(2) [19.4-27.4]) received 2 g of intravenous acetaminophen. Fifteen blood samples were collected per patient. Population pharmacokinetic modelling was performed using NONMEM.

Results: In morbidly obese patients, the median area under the plasma concentration-time curve from 0 to 8 h (AUC0-8h) of acetaminophen was significantly smaller (P = 0.009), while the AUC0-8h ratios of the glucuronide, sulphate and cysteine metabolites to acetaminophen were significantly higher (P = 0.043, 0.004 and 0.010, respectively). In the model, acetaminophen CYP2E1-mediated clearance (cysteine and mercapturate) increased with lean body weight [LBW] (population mean [relative standard error] 0.0185 L/min [15 %], P < 0.01). Moreover, accelerated formation of the cysteine and mercapturate metabolites was found with increasing LBW (P < 0.001). Glucuronidation clearance (0.219 L/min [5 %]) and sulphation clearance (0.0646 L/min [6 %]) also increased with LBW (P < 0.001).

Conclusion: Obesity leads to lower acetaminophen concentrations and earlier and higher peak concentrations of acetaminophen cysteine and mercapturate. While a higher dose may be anticipated to achieve adequate acetaminophen concentrations, the increased CYP2E1-mediated pathway may preclude this dose adjustment.

Fig. 1

Schematic illustration of the population pharmacokinetic model. CL _unchanged unchanged clearance of acetaminophen, CL _gluc glucuronidation clearance, CL _sulp sulphation clearance, CL _CYP2E1 CYP2E1-mediated clearance, CL _{E gluc} glucuronide elimination clearance, CL _{E sulph} sulphate elimination clearance, CL _{E cys&mercap} cysteine & mercapturate elimination clearance, Ktr _CYP2E1 CYP2E1 transit compartment rate constant, Ktr _gluc glucuronide transit compartment rate constant, Q inter-compartmental clearance of acetaminophen sulphate between the central and peripheral compartment, V volume of distribution

Fig. 2

Area under the plasma concentration–time curve from 0 to 8 h (AUC_0–8h) metabolite-to-acetaminophen ratios of a acetaminophen glucuronide, b acetaminophen sulphate, c acetaminophen cysteine and d acetaminophen mercapturate in non-obese patients (n = 7) versus morbidly obese patients (n = 20) after a 2 g intravenous acetaminophen dose. *P < 0.05 (Mann–Whitney test)

Fig. 3

Empirical Bayes estimates for morbidly obese patients (n = 20; black circles) and non-obese patients (n = 8; grey circles) versus lean body weight (LBW), including a glucuronidation clearance (CL_gluc), b sulphation clearance (CL_sulph) and c cytochrome P450 2E1–mediated clearance (CL_CYP2E1) [base pharmacokinetic model]

Fig. 4

Observed versus individual-predicted and observed versus population-predicted concentrations of acetaminophen (top row), acetaminophen glucuronide (second row), acetaminophen sulphate (third row) and acetaminophen cysteine and mercapturate (bottom row) in the final model for morbidly obese patients (n = 20; black circles) and non-obese patients (n = 8; grey circles). Ln log-normal

Fig. 5

Visual predictive checks of the final model for acetaminophen (top row), acetaminophen glucuronide (second row), acetaminophen sulphate (third row) and acetaminophen cysteine and mercapturate [cys and mercap] (bottom row) in morbidly obese patients (left graphs) and non-obese patients (right graphs). The observed concentrations are shown as blue circles, and the medians (and 2.5th and 97.5th percentiles) of the observed data are shown as solid red lines (and lower and upper dashed red lines, respectively). The pink shaded areas represent the 95 % confidence intervals for the medians of the simulated concentrations (n = 1000), based on the original data set, and the lower and upper blue shaded areas represent the 95 % confidence intervals of the 2.5th and 97.5th percentiles, respectively

Fig. 6

Population-predicted acetaminophen concentrations (first graph), acetaminophen glucuronide concentrations (second graph), acetaminophen sulphate concentrations (third graph) and acetaminophen cysteine and mercapturate concentrations (fourth graph) over time in one non-obese patient (with total body weight [TBW] of 60.1 kg and lean body weight [LBW] of 41.2 kg) and in three morbidly obese patients (with TBWs of 106, 134 and 193 kg; and with LBWs of 51.3, 65.8 and 96.2 kg, respectively) after 2 g of intravenous acetaminophen