Département de santé environnementale et santé au travail, Université de Montréal, Montréal, Québec, Canada.
J Appl Toxicol. 2010 Jul;30(5):437-49. doi: 10.1002/jat.1515.
The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for p-tert-octylphenol (OP) for understanding the qualitative and quantitative determinants of its kinetics in Sprague-Dawley rats. Compartments of the PBPK model included the liver, richly perfused tissues, poorly perfused tissues, reproductive tissues, adipose tissue and subcutaneous space, in which OP uptake was described as a blood flow- or a membrane diffusion-limited process. The PBPK model successfully simulated previously published data on blood and tissue OP concentrations in Sprague-Dawley rats following oral, intravenous (i.v.) or subcutaneous (s.c.) routes. The model predicted that OP concentrations would reach 6.8, 13.8 and 27.9 ng ml(-1) (male) and 7.2, 14.7 and 31.4 ng ml(-1) (female), 4 h after a single i.v. dose of 2, 4 and 8 mg kg(-1), respectively. The model also predicted that OP concentrations would reach 53.3, 134.8 and 271.2 ng ml(-1) (male) and 87.4, 221.4 and 449.7 ng ml(-1) (female) 4 h after a single oral dose (50, 125 and 250 mg kg(-1)) and that, 4 h after a single s.c. dose (125 mg kg(-1)), OP concentrations would reach 111.3 ng ml(-1) (male) and 121.6 ng ml(-1). A marked sex difference was seen in blood and tissue OP concentrations. This was reflected in the model by a gender-specific maximal velocity of metabolism (V(max)) that was higher (1.77 x) in male than in female rats. Further studies are required to elucidate the mechanism underlying the gender differences and to evaluate whether that is also observed in humans.
本研究旨在建立对叔辛基苯酚（OP）的生理药代动力学（PBPK）模型，以了解其在 Sprague-Dawley 大鼠体内动力学的定性和定量决定因素。PBPK 模型的隔室包括肝脏、富含血液的组织、血液灌注不良的组织、生殖组织、脂肪组织和皮下空间，其中 OP 的摄取被描述为血流或膜扩散限制过程。PBPK 模型成功地模拟了先前发表的 Sprague-Dawley 大鼠口服、静脉（i.v.）或皮下（s.c.）给予 OP 后血液和组织 OP 浓度的数据。该模型预测，静脉注射 2、4 和 8 mg kg(-1) 后，雄性大鼠 4 小时后的 OP 浓度将分别达到 6.8、13.8 和 27.9 ng ml(-1)，雌性大鼠则分别达到 7.2、14.7 和 31.4 ng ml(-1)；单次口服 50、125 和 250 mg kg(-1) 后，雄性大鼠 4 小时后的 OP 浓度将分别达到 53.3、134.8 和 271.2 ng ml(-1)，雌性大鼠则分别达到 87.4、221.4 和 449.7 ng ml(-1)；单次皮下注射 125 mg kg(-1) 后，雄性大鼠 4 小时后的 OP 浓度将达到 111.3 ng ml(-1)，雌性大鼠则达到 121.6 ng ml(-1)。OP 在血液和组织中的浓度存在显著的性别差异，这在模型中反映为雄性大鼠的代谢最大速率（V(max)）比雌性大鼠高（1.77 倍）。需要进一步研究以阐明性别差异的机制，并评估其是否也存在于人类中。
