整合度依赖性毒性数据和毒动力学,以告知肝毒性反应途径
Daniel P Russo1, Lauren M Aleksunes2, Katy Goyak3
1Department of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey 08028, United States.
Environmental science & technology
|August 11, 2023
概括
开发新的计算模型来预测肝毒性 (肝毒性) 是至关重要的. 本研究提出了一种新的策略,使用高通量选试验来构建基于途径的模型,以改进化学安全评估.
科学领域:
- 计算毒理学计算毒理学
- 化学安全评估 化学安全评估
- 在体外毒理学.
背景情况:
- 动物模型往往无法预测人类肝脏的毒性.
- 试验室高通量查 (HTS) 试验提供了一个替代方案,但需要基于复杂毒性的途径模型.
- 现有的简单途径模型是成功的,但复杂的毒性,如肝毒性仍然具有挑战性.
研究的目的:
- 开发一种计算策略,用于为复杂毒性,特别是人类肝毒性创建基于途径的模型.
- 识别和分组相关的肝毒性机制的体外测定.
- 使用这些模型来改善体内肝毒性预测.
主要方法:
- 利用了2171种化学物质的数据库,并对人类肝毒性进行了分类.
- 选了1600多个ToxCast/Tox21 HTS测定,以确定与肝毒性相关的测定.
- 开发了一个计算框架,将测试分组为52个基于生物目标/机制的关键事件 (KE) 模型.
- 雇员监督学习与KE分数和毒性动力学信息进行预测.
主要成果:
- 确定了157个与人类肝毒性相关的HTS测定.
- 将测试分组为52个KE模型,生成化学功效的KE得分.
- 观察到,具有高KE分数的化学结构分组可能表明肝毒性机制.
- 通过整合KE得分和毒动力学数据,实现了 in vivo 肝毒性预测的改进.
结论:
- 开发的计算策略为基于复杂毒性的途径建模提供了一种通用方法.
- 这种方法提高了化学诱导的肝损伤的预测.
- 该战略有可能在化学毒性评估中得到更广泛的应用.
相关概念视频
Toxic Reactions: Overview
1.0K
When toxic substances penetrate the human body, they disseminate to various tissues, undergoing metabolic changes. This process yields reactive metabolites that may covalently bind with specific target molecules, resulting in toxicity.
Toxicity falls into two primary categories: local and systemic.
Local toxicity appears at the exposure site, such as protein denaturation caused by caustic substances.
In contrast, systemic toxicity requires the toxic agent's absorption and distribution,...
Toxicity falls into two primary categories: local and systemic.
Local toxicity appears at the exposure site, such as protein denaturation caused by caustic substances.
In contrast, systemic toxicity requires the toxic agent's absorption and distribution,...
1.0K
Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
61
Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.
A recent model describes pravastatin's hepatobiliary excretion,...
A recent model describes pravastatin's hepatobiliary excretion,...
61
Drug Concentration Versus Time Correlation
875
The plasma drug concentration-time curve is a crucial tool in pharmacokinetics, representing the drug's concentration in plasma at different time intervals post-administration. This curve illustrates the drug's journey from absorption into the systemic circulation, distribution to body tissues, and eventual elimination through excretion or biotransformation.
Two pivotal parameters are the minimum effective concentration (MEC) and the minimum toxic concentration (MTC). The MEC is the...
Two pivotal parameters are the minimum effective concentration (MEC) and the minimum toxic concentration (MTC). The MEC is the...
875
Phase II Reactions: Glutathione Conjugation and Mercapturic Acid Formation
257
Glutathione, a tripeptide made up of glutamate, cysteine, and glycine, is a critical player in the detoxification of drugs and xenobiotics via a process known as glutathione conjugation or mercapturic acid formation. This phase II biotransformation reaction involves the covalent binding of glutathione to a drug or its metabolite, enhancing the compound's water solubility and enabling its excretion.
Several distinctive characteristics distinguish glutathione conjugation from other phase II...
Several distinctive characteristics distinguish glutathione conjugation from other phase II...
257
Model-Independent Approaches for Pharmacokinetic Data: Noncompartmental Analysis
95
Noncompartmental analyses offer an alternative method for describing drug pharmacokinetics without relying on a specific compartmental model. In this approach, the drug's pharmacokinetics are assumed to be linear, with the terminal phase log-linear. This assumption allows for simplified analysis and interpretation of the drug's behavior in the body.
One important characteristic of noncompartmental analyses is that drug exposure increases proportionally with increasing doses. This...
One important characteristic of noncompartmental analyses is that drug exposure increases proportionally with increasing doses. This...
95
Pharmacokinetic Models: Comparison and Selection Criterion
104
Physiological and compartmental models are valuable tools used in studying biological systems. These models rely on differential equations to maintain mass balance within the system, ensuring an accurate representation of the dynamic processes at play.
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.
104


