van Rongen Anne, Välitalo Pyry A J, Peeters Mariska Y M, Boerma Djamila, Huisman Fokko W, van Ramshorst Bert, van Dongen Eric P A, van den Anker Johannes N, Knibbe Catherijne A J
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.
Clin Pharmacokinet. 2016 Jul;55(7):833-847. doi: 10.1007/s40262-015-0357-0.
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.
对乙酰氨基酚主要通过葡萄糖醛酸化和硫酸化进行代谢，而经由细胞色素P450（CYP）2E1的次要代谢途径则被认为是导致肝毒性的原因。据报道，肥胖患者体内CYP2E1活性会被诱导，从而可能使对乙酰氨基酚的安全性降低。本研究的目的是确定病态肥胖和非肥胖患者体内对乙酰氨基酚及其代谢产物（葡萄糖醛酸苷、硫酸盐、半胱氨酸和硫醚氨酸）的药代动力学。
20例病态肥胖患者（总体重[TBW]中位数为140.1千克[范围106 - 193.1千克]，体重指数[BMI]为45.1千克/平方米[40 - 55.2千克/平方米]）和8例非肥胖患者（TBW为69.4千克[53.4 - 91.7]，BMI为21.8千克/平方米[19.4 - 27.4]）接受了2克静脉注射对乙酰氨基酚。每位患者采集15份血样。使用NONMEM进行群体药代动力学建模。
在病态肥胖患者中，对乙酰氨基酚在0至8小时血浆浓度 - 时间曲线下的面积中位数（AUC0 - 8h）显著较小（P = 0.009），而葡萄糖醛酸苷、硫酸盐和半胱氨酸代谢产物与对乙酰氨基酚的AUC0 - 8h比值显著更高（分别为P = 0.043、0.004和0.010）。在模型中，对乙酰氨基酚CYP2E1介导的清除率（半胱氨酸和硫醚氨酸）随瘦体重[LBW]增加而升高（群体均值[相对标准误差]为0.0185升/分钟[15%]，P < 0.01）。此外，发现随着LBW增加，半胱氨酸和硫醚氨酸代谢产物的形成加速（P < 0.001）。葡萄糖醛酸化清除率（0.219升/分钟[5%]）和硫酸化清除率（0.0646升/分钟[6%]）也随LBW增加而升高（P < 0.001）。
肥胖导致对乙酰氨基酚浓度降低，对乙酰氨基酚半胱氨酸和硫醚氨酸的峰值浓度出现得更早且更高。虽然可能需要更高剂量以达到足够的对乙酰氨基酚浓度，但CYP2E1介导途径的增加可能使这种剂量调整不可行。
