相关实验视频

Updated: May 5, 2026

Generation of a Humanized Mouse Liver Using Human Hepatic Stem Cells

Generation of a Humanized Mouse Liver Using Human Hepatic Stem Cells

Published on: August 29, 2016

使用人性化小鼠对尿素二酸盐-葡萄糖转移酶基质药物处置的定量预测

Taiji Miyake¹, Yuito Fujita¹, Manabu Hirabayashi²

¹Pharmaceutical Science Department, Translational Research Division, Chugai Pharmaceutical Co., Ltd., Yokohama-shi, Japan.

Drug metabolism and disposition: the biological fate of chemicals

|March 7, 2025

概括

人类肝脏仿真小鼠 (hu-PXB) 准确地预测了由尿素二酸盐-葡萄糖转酶 (UGT) 酶介导的药物清除. 该模型改进了用于评估人类药物处置和药物相互作用的体外方法.

科学领域:

药理动力学和药物新陈代谢
肝病学和再生医学肝病学和再生医学
翻译药理学翻译药理学

背景情况:

准确预测药物清除和药物相互作用对于药理动力学至关重要.
当前的体外和动物模型往往无法准确预测由代谢酶,特别是尿素二酸盐-葡萄糖转移酶 (UGT) 介导的药物排放.

研究的目的:

用hu-PXB小鼠对人类中介的UGT药物处置的可预测性进行评估.
评估hu-PXB小鼠在预测UGT介导的药物相互作用中的有用性.

主要方法:

在试验室中,使用冷保存的人类肝细胞和UGT基质估计了人类肝脏内在清除 (CLh,int).
在体内,CLh,int通过静脉注射UGT基质给hu-PXB小鼠和SCID小鼠来确定,并将结果与人类数据进行比较.
通过向hu-PXB小鼠注射UGT基质,包括或不含probenecid (一种UGT抑制剂),对UGT介导的药物相互作用进行了评估.

主要成果:

在体外肝细胞测定显著低于预测的人类CLh,int.
胡-PXB小鼠与人类的CLh,int有很强的相关性 (R2 = 0.95),表现优于SCID小鼠 (R2 = 0.69).
胡-PXB小鼠预测UGT基质药物CLh,int在临床值的2倍之内,并准确地反映了在人类中观察到的probenecid诱导的清除变化.

结论:

使用hu-PXB小鼠的体内研究提供了一种可靠的方法来预测由UGT.B调解的人类药物处置.
胡-PXB小鼠是预测UGT介导药物相互作用的宝贵工具.
这些发现支持在药物发现中使用hu-PXB小鼠来选择更好的候选药物,并在临床实践中用于精确的药理动力学建模.

关键词:

清除许可证的情况药物相互作用药物相互作用人性化动物的人性化动物尿素二酸盐 - 葡萄糖诺西尔转移酶

更多相关视频

Assessment of Kidney Function in Mouse Models of Glomerular Disease

Assessment of Kidney Function in Mouse Models of Glomerular Disease

Published on: June 30, 2018

Highly Sensitive Measurement of Glomerular Permeability in Mice with Fluorescein Isothiocyanate-polysucrose 70

Highly Sensitive Measurement of Glomerular Permeability in Mice with Fluorescein Isothiocyanate-polysucrose 70

Published on: August 9, 2019

相关概念视频

Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance

Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance

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,...

Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes

Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes

Cytochrome P450 (CYP450) enzymes are a superfamily of heme-containing monooxygenases that play a pivotal role in Phase I drug metabolism by catalyzing oxidation and reduction reactions.These enzymes transform lipophilic xenobiotics into more hydrophilic metabolites, facilitating subsequent Phase II conjugation and eventual excretion. The CYP450 family is classified into families (e.g., CYP1–CYP3) and subfamilies (e.g., CYP2A, CYP2C), based on amino acid sequence homology.CYP450...

Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase

Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase

Phase II biotransformation reactions are essential for detoxifying and eliminating xenobiotics, including many pharmaceutical compounds. These reactions typically involve conjugation, the covalent attachment of polar endogenous groups such as glucuronic acid, sulfate, methyl, or acetyl moieties to functional groups introduced during Phase I metabolism. The resulting conjugates are more water-soluble, enabling efficient renal or biliary excretion.The major classes of Phase II enzymes include...