Csanády G A, Mendrala A L, Nolan R J, Filser J G
GSF-Institut für Toxikologie, Neuherberg, Oberschleissheim, Germany.
Arch Toxicol. 1994;68(3):143-57. doi: 10.1007/BF03035414.
Concern about the carcinogenic potential of styrene (ST) is due to its reactive metabolite, styrene-7,8-oxide (SO). To estimate the body burden of SO resulting from various scenarios, a physiologically based pharmacokinetic (PBPK) model for ST and its metabolite SO was developed. This PBPK model describes the distribution and metabolism of ST and SO in the rat, mouse and man following inhalation, intravenous (i.v.), oral (p.o.) and intraperitoneal (i.p.) administration of ST or i.v., p.o. and i.p. administration of SO. Its structure includes the oxidation of ST to SO, the intracellular first-pass hydrolysis of SO catalyzed by epoxide hydrolase and the conjugation of SO with glutathione. This conjugation is described by an ordered sequential ping-pong mechanism between glutathione, SO and glutathione S-transferase. The model was based on a PBPK model constructed previously to describe the pharmacokinetics of butadiene with its metabolite butadiene monoxide. The equations of the original model were revised to refer to the actual tissue concentration of chemicals instead of their air equivalents used originally. Blood:air and tissue:blood partition coefficients for ST and SO were determined experimentally and have been published previously. Metabolic parameters were taken from in vitro or in vivo measurements. The model was validated using various data sets of different laboratories describing pharmacokinetics of ST and SO in rodents and man. In addition, the influences of the biochemical parameters, alveolar ventilation and blood:air ventilation and blood:air partition coefficient for ST on the pharmacokinetics of ST and SO were investigated by sensitivity analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
对苯乙烯（ST）致癌潜力的担忧源于其活性代谢物苯乙烯-7,8-氧化物（SO）。为了估计各种情况下SO的体内负荷，开发了一种基于生理学的苯乙烯及其代谢物SO的药代动力学（PBPK）模型。该PBPK模型描述了大鼠、小鼠和人类在吸入、静脉注射（i.v.）、口服（p.o.）和腹腔注射（i.p.）ST或静脉注射、口服和腹腔注射SO后ST和SO的分布与代谢。其结构包括ST氧化为SO、环氧水解酶催化的SO细胞内首过水解以及SO与谷胱甘肽的结合。这种结合通过谷胱甘肽、SO和谷胱甘肽S-转移酶之间的有序顺序乒乓机制来描述。该模型基于先前构建的用于描述丁二烯及其代谢物丁二烯 monoxide药代动力学的PBPK模型。对原始模型的方程进行了修订，以参考化学物质的实际组织浓度而非最初使用的空气当量。通过实验测定了ST和SO的血：气和组织：血分配系数，并已在之前发表。代谢参数取自体外或体内测量值。使用不同实验室描述ST和SO在啮齿动物和人类中药代动力学的各种数据集对该模型进行了验证。此外，通过敏感性分析研究了生化参数、肺泡通气以及ST的血：气和血：气分配系数对ST和SO药代动力学的影响。（摘要截短于250字）
