Identification of drug-pollutant interactions and refining predictions of interindividual variability in pollutant toxicokinetics

药物-污染物相互作用的鉴定和污染物毒代动力学个体间变异性的精确预测

• 批准号: 311900-2010
• 负责人: Haddad, Sami
• 金额: $ 1.97万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=506462
• 关键词: Identification; drug; pollutant; interactions; refining

A problem that arises when attempting to predict toxicity levels in humans is that, for a given dose of toxicant, there exists interindividual variability in the fraction of dose that attains the target tissue and therefore leading to variability in the response. In order to adequately predict the toxicity of a compound following exposure, it is necessary to use adequate tools to estimate kinetics of the chemical in the target tissue. In recent years, physiologically based toxicokinetic/pharmacokinetic (PBPK) modeling has been used to this effect. In order to better estimate/consider interindividual variability, these models can take into account factors that are intrinsic to individuals which are related to their physiology (e.g., age, gender, adiposity) and their genetics (e.g., enzymatic polymorphisms). They can also consider extrinsic factors such as coexposure to other xenobiotics leading to toxicokinetic interactions. Different lifestyles can favor repeated coexposures to xenobiotics, such as chronic medication. The principal objective of this research program is to increase our knowledge on the factors that modulate toxicokinetics of environmental toxicants in order to refine predictability in tissue exposure assessment using PBPK modeling. The proposed program aims to: (i) identify and characterize drug-pollutant metabolic interactions by in vitro methods using rat and human material; (ii) validate PBPK modeling in vitro-in vivo extrapolation approaches using drug-pollutant toxicokinetic interactions with data obtained from rat in vivo exposures; (iii) develop methods to estimate metabolic variability in population based on available in vitro data; and (iv) confirm and refine variability estimations in adipose tissue volumes. The undertaking of such a research program will greatly enhance our knowledge on how drug consumption can affect the variability in the body's response to environmental pollution. The development of such drug-pollutant physiologically-based toxicokinetic interactions models will lead to improvements in Canadian human health risk assessment practices. With this program, Canadian research will be leading in the field of PBPK modeling of toxicokinetic interactions and interindividual variability.

在试图预测人体毒性水平时出现的一个问题是，对于给定剂量的毒物，到达靶组织的剂量分数存在个体间差异，因此导致反应的差异。为了充分预测化合物暴露后的毒性，有必要使用适当的工具来估计化学品在靶组织中的动力学。近年来，基于生理学的毒代动力学/药代动力学（PBPK）模型已被用于这一效果。为了更好地估计/考虑个体间变异性，这些模型可以考虑与其生理学相关的个体固有的因素（例如，年龄、性别、肥胖）和它们的遗传学（例如，酶多态性）。他们还可以考虑外部因素，如共同暴露于其他异生物质，导致毒代动力学相互作用。不同的生活方式可能有利于重复共同暴露于外源性物质，如慢性药物治疗。这项研究计划的主要目标是增加我们的知识，调节环境毒物的toxicoketics的因素，以改善组织暴露评估使用PBPK建模的可预测性。拟议方案旨在：（i）使用大鼠和人体材料，通过体外方法确定和表征药物-污染物代谢相互作用;（ii）使用从大鼠体内暴露获得的数据，使用药物-污染物毒代动力学相互作用，验证体外-体内外推方法中的PBPK建模;（iii）根据现有体外数据，开发估计人群代谢变异性的方法;以及（iv）确认和改进脂肪组织体积的可变性估计。开展这样一项研究计划将大大提高我们对药物消费如何影响人体对环境污染反应的可变性的认识。这种药物污染物的生理为基础的毒代动力学相互作用模型的发展将导致加拿大人类健康风险评估的做法。通过该计划，加拿大的研究将在毒代动力学相互作用和个体间变异性的PBPK建模领域处于领先地位。