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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 7/2016

Open Access 01-07-2016 | Original Research Article

Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen

Authors: Anne van Rongen, Pyry A. J. Välitalo, Mariska Y. M. Peeters, Djamila Boerma, Fokko W. Huisman, Bert van Ramshorst, Eric P. A. van Dongen, Johannes N. van den Anker, Catherijne A. J. Knibbe

Published in: Clinical Pharmacokinetics | Issue 7/2016

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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/m2 [40–55.2 kg/m2]) and eight non-obese patients (with a TBW of 69.4 kg [53.4–91.7] and BMI of 21.8 kg/m2 [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.
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Metadata
Title
Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen
Authors
Anne van Rongen
Pyry A. J. Välitalo
Mariska Y. M. Peeters
Djamila Boerma
Fokko W. Huisman
Bert van Ramshorst
Eric P. A. van Dongen
Johannes N. van den Anker
Catherijne A. J. Knibbe
Publication date
01-07-2016
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 7/2016
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-015-0357-0

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