title: Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands.|Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Anne
authors.initials: A
authors.lastname: van Rongen
authors.affiliation: Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Pyry A J
authors.initials: PAJ
authors.lastname: Välitalo
authors.affiliation: Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands.
authors.forename: Mariska Y M
authors.initials: MYM
authors.lastname: Peeters
authors.affiliation: Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Djamila
authors.initials: D
authors.lastname: Boerma
authors.affiliation: Department of Oral and Maxillofacial Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Fokko W
authors.initials: FW
authors.lastname: Huisman
authors.affiliation: Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: van Ramshorst
authors.affiliation: Department of Anesthesiology and Intensive Care, St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Eric P A
authors.initials: EPA
authors.lastname: van Dongen
authors.affiliation: Division of Clinical Pharmacology, Children's National Medical Center, Washington DC, USA.|Department of Pediatric Pharmacology, University Children's Hospital, Basel, Switzerland.|Intensive Care and Department of Pediatric Surgery, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Johannes N
authors.initials: JN
authors.lastname: van den Anker
authors.affiliation: Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands. c.knibbe@antoniusziekenhuis.nl.|Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands. c.knibbe@antoniusziekenhuis.nl.
authors.forename: Catherijne A J
authors.initials: CAJ
authors.lastname: Knibbe
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D015992:Body Mass Index; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009767:Obesity, Morbid / Q000378:metabolism*; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D000082:Acetaminophen; C069744:acetaminophen cysteine; D019392:Cytochrome P-450 CYP2E1; D003545:Cysteine
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