| Title |
Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen
|
|---|---|
| Published in |
Clinical Pharmacokinetics, January 2016
|
| DOI | 10.1007/s40262-015-0357-0 |
| Pubmed ID | |
| 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 |
| 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. |
X Demographics
The data shown below were collected from the profiles of 4 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Spain | 2 | 50% |
| Netherlands | 1 | 25% |
| Unknown | 1 | 25% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 3 | 75% |
| Practitioners (doctors, other healthcare professionals) | 1 | 25% |
Mendeley readers
The data shown below were compiled from readership statistics for 73 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 73 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Master | 14 | 19% |
| Researcher | 13 | 18% |
| Student > Ph. D. Student | 10 | 14% |
| Other | 4 | 5% |
| Student > Bachelor | 4 | 5% |
| Other | 11 | 15% |
| Unknown | 17 | 23% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 21 | 29% |
| Pharmacology, Toxicology and Pharmaceutical Science | 21 | 29% |
| Nursing and Health Professions | 3 | 4% |
| Sports and Recreations | 2 | 3% |
| Agricultural and Biological Sciences | 2 | 3% |
| Other | 4 | 5% |
| Unknown | 20 | 27% |
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 04 February 2016.
All research outputs
#13,455,370
of 22,842,950 outputs
Outputs from Clinical Pharmacokinetics
#1,092
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Outputs of similar age
#191,275
of 396,850 outputs
Outputs of similar age from Clinical Pharmacokinetics
#8
of 16 outputs
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