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Effect of Hepatic Disease on Pharmacokinetics: Pathophysiologic Assessment and Liver Function Test01:22

Effect of Hepatic Disease on Pharmacokinetics: Pathophysiologic Assessment and Liver Function Test

180
In clinical practice, the direct measurement of hepatic blood flow to evaluate liver function presents significant challenges due to the intricate and specialized nature of the necessary techniques. Consequently, healthcare professionals often rely on empirical estimates derived from thorough patient examinations and liver function tests to gauge liver health. Among the tools at their disposal, the Child–Pugh and MELD scoring systems stand out for their ability to categorize and assess...
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Effect of Hepatic Disease on Pharmacokinetics: Drug Dosing and Hepatic Blood Flow01:26

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Chronic liver disease significantly impacts drug metabolism due to alterations in hepatic blood flow and enzyme accessibility. This disruption affects the body's pharmacokinetics—the movement and processing of drugs within the system. Key enzymes crucial for metabolizing medications become less accessible, changing how drugs are processed and utilized. Furthermore, liver disease influences the synthesis of plasma proteins, such as albumin and globulins, which play critical roles in drug...
212
Effect of Hepatic Disease on Pharmacokinetics: Active Drug, Metabolite and Fraction of Metabolized Drug01:14

Effect of Hepatic Disease on Pharmacokinetics: Active Drug, Metabolite and Fraction of Metabolized Drug

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In pharmacotherapy, monitoring drug concentrations is paramount, especially for drugs whose therapeutic effects hinge on both the active compound and its metabolite. Hepatic impairment profoundly influences drug potency by altering liver function. If the drug is more potent than its metabolite, impaired liver function amplifies drug activity due to elevated drug concentration levels. Conversely, if the metabolite holds greater potency, diminished liver function diminishes drug activity by...
212
Effect of Hepatic Disease on Pharmacokinetics: Dose Adjustments Due to Hepatic Impairment01:08

Effect of Hepatic Disease on Pharmacokinetics: Dose Adjustments Due to Hepatic Impairment

253
Hepatic impairment, characterized by decreased liver function, does not uniformly mandate adjustments in drug dosage. Whether dosage modifications are necessary depends on various factors related to the drug's metabolism and elimination pathways. If a drug is primarily excreted via the kidneys and bypasses significant hepatic processing, if it undergoes minimal metabolic transformation in the liver, or if it is volatile and primarily expelled through the lungs, dose adjustments may not be...
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Hepatic Drug Excretion: Influencing Factors01:16

Hepatic Drug Excretion: Influencing Factors

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The biliary system of the liver, crucial for bile secretion and drug excretion, comprises intrahepatic bile ducts that merge to form the common hepatic duct. This duct, carrying hepatic bile, combines with the cystic duct, draining the gallbladder and forming the common bile duct, which empties into the duodenum. Bile, produced by hepatic cells lining the bile canaliculi, is composed primarily of water, bile salts, pigments, electrolytes, and lesser amounts of cholesterol and fatty acids. Bile...
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Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance01:07

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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,...
277

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TCN-RDP:从时间序列毒基因组数据预测药物诱导的肝损伤

Zhongyan Zhao1, Bin Li2, Haochen Zuo1

  • 1College of Intelligence and Computing, Tianjin University, Tianjin 300350, China.

Journal of chemical information and modeling
|October 7, 2025
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概括

一个新的模型,TCN-RDP,使用基因表达数据准确预测药物诱导的肝损伤 (DILI). 这种计算方法提高了早期药物安全性评估,并减少了临床试验失败.

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科学领域:

  • 生物医学信息学 生物医学信息学
  • 计算毒理学计算毒理学
  • 药物基因组学 药物基因组学

背景情况:

  • 药物诱导性肝损伤 (DILI) 在药物开发中构成了重大挑战,导致临床试验失败率高.
  • 目前的毒理学评估是耗时和昂贵的,阻碍了早期的肝毒性预测.
  • 开发有效和准确的早期DILI检测方法对于药物安全至关重要.

研究的目的:

  • 介绍TCN-RDP,一种用于早期肝毒性预测的新型计算模型.
  • 利用时间卷积网络 (TCN) 和随机维度转换 (RDP) 来改进基因表达数据的分析.
  • 提高DILI预测模型的可解释性和准确性.

主要方法:

  • 时间卷积网络 (TCN) 的整合,以分析基因表达数据中的时间依赖性.
  • 随机维度转换 (RDP) 的应用,以有效地建模高维基因相互作用.
  • 使用基于XGBoost的特征选择算法来识别影响肝毒性的关键基因.

主要成果:

  • 在药物诱导的肝损伤方面,TCN-RDP模型实现了84.05%的高预测准确度.
  • 该模型展示了功能表征的改进,并捕获了复杂的基因相互作用.
  • 综合基因选择算法增强了模型的生物解释性.

结论:

  • TCN-RDP为早期肝毒性预测提供了一个生物学上可解释和有效的框架.
  • 与传统方法相比,该模型提供了更精确的药物安全性评估方法.
  • 未来的研究将专注于用人源数据验证模型,并为监管应用改进毒性分层.