Department I of Pharmacology, Center for Pharmacology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Department of Clinical Chemistry and Pharmacology, Linköping University, Linköping, Sweden.
J Clin Pharmacol. 2023 Jun;63(6):681-694. doi: 10.1002/jcph.2205. Epub 2023 Feb 17.
The pharmacokinetics (PK) of ethanol are important in pharmacology and therapeutics because of potential drug-alcohol interactions as well as in forensic science when alcohol-related crimes are investigated. The PK of ethanol have been extensively studied since the 1930s, although some issues remain unresolved, such as the significance of first-pass metabolism, whether zero-order kinetics apply, and the effects of food on bioavailability. We took advantage of nonlinear mixed-effects modeling to describe blood-alcohol concentration (BAC) profiles derived from 3 published clinical studies involving oral, intraduodenal, and intravenous administration of ethanol with and without food. The overall data set included 1510 BACs derived from 72 healthy subjects (60 men, 12 women) aged between 20 and 60 years. Two-compartment models with first-order absorption and Michaelis-Menten elimination kinetics adequately described the BAC profiles. Food intake had 2 separate effects: It reduced the absorption rate constant and accelerated the maximum elimination rate. Estimates of the maximum elimination rate (fasted) and the food effect (as a factor) were 6.31 g/h (95%CI, 6.04-6.59 g/h) and 1.39-fold (95%CI, 1.33-1.46-fold), respectively. Simulations showed that the area under the BAC-time curve (AUC) was smaller with lower input rate of ethanol, irrespective of any first-pass metabolism. The AUC from time 0 to 10 hours for a 75-kg subject was 2.34 g • h/L (fed) and 3.83 g • h/L (fasted) after an oral dose of 45 g ethanol. This difference was mainly attributable to the food effect on ethanol elimination and depended less on the absorption rate. Our new approach to explain the complex human PK of ethanol may help when BAC predictions are made in clinical pharmacology and forensic medicine.
乙醇的药代动力学（PK）在药理学和治疗学中很重要，因为药物与酒精相互作用的潜在风险，以及在涉及酒精相关犯罪的法医学中也很重要。自 20 世纪 30 年代以来，乙醇的 PK 已经得到了广泛的研究，尽管一些问题仍然没有得到解决，例如首过代谢的意义、是否适用零级动力学以及食物对生物利用度的影响。我们利用非线性混合效应模型来描述来自 3 项已发表的临床研究的血液酒精浓度（BAC）曲线，这些研究涉及口服、十二指肠内和静脉给予乙醇，以及是否同时给予食物。整个数据集包括来自 72 名年龄在 20 至 60 岁之间的健康受试者的 1510 个 BAC 值。具有一级吸收和米氏消除动力学的两室模型充分描述了 BAC 曲线。食物摄入有两个独立的作用：它降低了吸收速率常数并加速了最大消除速率。最大消除速率（禁食）和食物效应（作为一个因子）的估计值分别为 6.31 g/h（95%CI，6.04-6.59 g/h）和 1.39 倍（95%CI，1.33-1.46 倍）。模拟结果表明，BAC-时间曲线下面积（AUC）较小，乙醇输入率较低，无论是否存在首过代谢。75 公斤体重的受试者口服 45 克乙醇后，10 小时内的 AUC 为 2.34 g·h/L（进食）和 3.83 g·h/L（禁食）。这种差异主要归因于食物对乙醇消除的影响，而对吸收速率的影响较小。我们解释复杂的人体乙醇 PK 的新方法可能有助于在临床药理学和法医学中进行 BAC 预测。
