Frederick C B, Potter D W, Chang-Mateu M I, Andersen M E
Toxicology Department, Rohm and Haas Company, Spring House, Pennsylvania 19477.
Toxicol Appl Pharmacol. 1992 Jun;114(2):246-60. doi: 10.1016/0041-008x(92)90075-4.
A physiologically based pharmacokinetic and pharmacodynamic model has been developed to describe the absorption, distribution, and metabolism of orally dosed ethyl acrylate. The model describes the metabolism of ethyl acrylate in 14 tissues based on in vitro metabolic studies conducted with tissue homogenates. The routes of metabolism included in the model are carboxylesterase-catalyzed ester hydrolysis, conjugation with glutathione, and binding to protein. To adequately describe the rate and extent of glutathione depletion following gavage dosing, the steady-state rate of glutathione synthesis in the organs of interest was included. In vivo validation of the model was conducted by comparing the predictions of the model to the results of a variety of gavage dosing experiments with ethyl acrylate, including (1) the time course of glutathione depletion in a variety of tissues up to 98 hr following dosing at three dose levels, (2) the rate and extent of radiolabeled carbon dioxide excretion, and (3) protein binding in the forestomach. The very rapid metabolism predicted by the model was consistent with the observation that ethyl acrylate was metabolized too rapidly in vivo to be detected by common analytical techniques for tissue metabolite analysis. The validation data indicated that the model provides a reasonable description of the pharmacokinetics and the pharmacodynamic response of specific rat tissues following gavage dosing of ethyl acrylate. A dose surrogate, or measure of delivered dose, for ethyl acrylate was calculated and correlated with the incidence and severity of contact site toxicity (edema, inflammation, ulceration, and hyperplasia). The model provides a quantitative tool for evaluating exposure scenarios for their potential to induce contact-site toxicity, and it provides a quantitative approach for understanding the lack of toxicity in tissues remote from the dosing site.
已建立一个基于生理学的药代动力学和药效学模型，以描述口服给药的丙烯酸乙酯的吸收、分布和代谢。该模型基于用组织匀浆进行的体外代谢研究，描述了丙烯酸乙酯在14种组织中的代谢情况。模型中包括的代谢途径有羧酸酯酶催化的酯水解、与谷胱甘肽结合以及与蛋白质结合。为了充分描述灌胃给药后谷胱甘肽消耗的速率和程度，纳入了感兴趣器官中谷胱甘肽合成的稳态速率。通过将模型预测结果与各种丙烯酸乙酯灌胃给药实验的结果进行比较，对模型进行了体内验证，这些实验包括：(1) 在三个剂量水平给药后长达98小时，多种组织中谷胱甘肽消耗的时间进程；(2) 放射性标记二氧化碳排泄的速率和程度；(3) 前胃中的蛋白质结合。模型预测的非常快速的代谢与以下观察结果一致，即丙烯酸乙酯在体内代谢太快，无法通过用于组织代谢物分析的常规分析技术检测到。验证数据表明，该模型对灌胃给予丙烯酸乙酯后特定大鼠组织的药代动力学和药效学反应提供了合理的描述。计算了丙烯酸乙酯的剂量替代指标或给药剂量测量值，并将其与接触部位毒性（水肿、炎症、溃疡和增生）的发生率和严重程度相关联。该模型提供了一种定量工具，用于评估暴露场景诱导接触部位毒性的潜力，并提供了一种定量方法来理解远离给药部位的组织中缺乏毒性的情况。
