Pharmacoenhancers for antiretroviral therapy: safety and future development

抗逆转录病毒治疗的药物增强剂：安全性和未来发展

• 批准号: 10170229
• 负责人: Xiaochao Ma
• 金额: $ 38.21万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-26 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170229
• 关键词: Acquired Immunodeficiency Syndrome; Biological Markers; Biological Sciences; Bypass; CYP3A4 gene; Chemical Structure; Clinical Trials; Critical Pathways; Data; Development; Dose; Drug Design; Future; Generations; Genetic Engineering; Hepatotoxicity; Human; Individual; International; Life; Ligands; Liver; Mediating; Metabolism; Modification; Mus; National Institute of Allergy and Infectious Disease; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Property; Receptor Activation; Regimen; Rifampin; Risk Factors; Ritonavir; Role; Safety; Series; Structure; Testing; Time; Transgenic Mice; analog; antiretroviral therapy; base; constitutive androstane receptor; drug metabolism; efavirenz; endoplasmic reticulum stress; environmental chemical; hepatotoxin; humanized mouse; improved; liver injury; metabolomics; mouse model; next generation; pregnane X receptor; public health relevance; transcription factor

ABSTRACT The objectives of this application are to determine the mechanisms of hepatotoxicity of the current available pharmacoenhancers and to provide a mechanism-based guidance for development of the next generation of pharmacoenhancers with less hepatotoxicity. Ritonavir (RTV) and cobicistat (COBI) are the first and second generations of pharmacoenhancers. RTV has been known as a hepatotoxin but its mechanism remains elusive. In a recent series of clinical trials, the hepatotoxicity of RTV was significantly potentiated in subjects who were pretreated with rifampicin (RIF) or efavirenz (EFV). Both RIF and EFV are potent ligands of human pregnane X receptor (PXR), a ligand-dependent transcription factor that upregulates Cytochrome P450 3A4 (CYP3A4) in drug metabolism. Because of the inter- species differences in ligand-dependent PXR activation, we generated a double transgenic mouse model expressing human PXR and CYP3A4 (TgCYP3A4/hPXR). By using the TgCYP3A4/hPXR mice, we recapitulated RTV hepatotoxicity that occurred in clinical trials. In addition, we found that COBI can cause similar liver damage as RTV. Furthermore, our metabolomic analysis revealed that RTV and COBI undergo the same bioactivation pathways to generate toxic metabolites, which are produced by CYP3A4. Based on these preliminary data, we hypothesize that human PXR modulates RTV/COBI hepatotoxicity through CYP3A4-mediated RTV/COBI bioactivation. We also hypothesize that structural modification to bypass the bioactivation pathways of RTV and COBI will mitigate their hepatotoxicity. To test our hypothesis, we propose the following three specific aims: (1) to determine the role of human PXR in RTV/COBI hepatotoxicity; (2) to determine the role of human CYP3A4 in RTV/COBI hepatotoxicity; and (3) to explore drug design for the next generation of pharmacoenhancers with less hepatotoxicity. Accomplishment of this project will have a significant impact on the field of pharmacoenhancers, especially for their safety and future development.

抽象的 本申请的目的是确定当前的肝毒性机制 现有的药物增强剂，并为下一步的开发提供基于机制的指导 产生肝毒性较小的药物增强剂。利托那韦 (RTV) 和考比司他 (COBI) 是 第一代和第二代药物增强剂。 RTV 被称为肝毒素，但它 机制仍然难以捉摸。在最近的一系列临床试验中，RTV 的肝毒性是 在用利福平（RIF）或依非韦伦（EFV）预处理的受试者中显着增强。两个都 RIF 和 EFV 是人孕烷 X 受体 (PXR) 的有效配体，PXR 是一种配体依赖性转录 药物代谢中上调细胞色素 P450 3A4 (CYP3A4) 的因子。由于间 配体依赖性PXR激活的物种差异，我们生成了双转基因小鼠模型 表达人 PXR 和 CYP3A4 (TgCYP3A4/hPXR)。通过使用 TgCYP3A4/hPXR 小鼠，我们 概括了临床试验中发生的 RTV 肝毒性。此外，我们发现COBI可以 引起与 RTV 类似的肝损伤。此外，我们的代谢组学分析表明 RTV 和 COBI 经历相同的生物激活途径产生有毒代谢物，由 CYP3A4 产生。 基于这些初步数据，我们假设人 PXR 调节 RTV/COBI 肝毒性 通过 CYP3A4 介导的 RTV/COBI 生物激活。我们还假设结构修饰 绕过RTV和COBI的生物激活途径将减轻它们的肝毒性。来测试我们的 假设，我们提出以下三个具体目标：（1）确定人类 PXR 在 RTV/COBI 肝毒性； (2)确定人CYP3A4在RTV/COBI肝毒性中的作用；和 (3)探索下一代肝毒性较小的药物增强剂的药物设计。 该项目的完成将对药物增强剂领域产生重大影响， 特别是为了他们的安全和未来的发展。

项目成果

Deficiency of N-acetyltransferase increases the interactions of isoniazid with endobiotics in mouse liver.

N-乙酰转移酶的缺乏会增加异烟肼与小鼠肝脏内生素的相互作用。

• 发表时间: 2017-12-01
• 影响因子: 5.8
• 作者: Wang, Pengcheng;Shehu, Amina I;Lu, Jie;Joshi, Rujuta H;Venkataramanan, Raman;Sugamori, Kim S;Grant, Denis M;Zhong, Xiao;Ma, Xiaochao
• 通讯作者: Ma, Xiaochao

Liver metabolomics in a mouse model of erythropoietic protoporphyria.

红细胞生成性原卟啉症小鼠模型的肝脏代谢组学。

• 发表时间: 2018
• 影响因子: 5.8
• 作者: Wang, Pengcheng;Sachar, Madhav;Guo, Grace L;Shehu, Amina I;Lu, Jie;Zhong, Xiao;Ma, Xiaochao
• 通讯作者: Ma, Xiaochao

Special Section on Drug Metabolism in Liver Injury and Repair Alterations of Cytochrome P450 – Mediated Drug Metabolism during Liver Repair and Regeneration after Acetaminophen-Induced Liver Injury in Mice S

肝损伤中的药物代谢和细胞色素 P450 的修复改变专题 — 对乙酰氨基酚诱导的小鼠肝损伤后肝脏修复和再生过程中介导的药物代谢

• 发表时间: 2024-09-14
• 作者: Yifan Bao;M. Phan;Junjie Zhu;Jos Xiaochao Ma;E. Manautou;Xiao
• 通讯作者: Xiao

Enzymes and Pathways of Kavain Bioactivation and Biotransformation.

卡瓦因生物活化和生物转化的酶和途径。

• 发表时间: 2019
• 影响因子: 4.1
• 作者: Wang, Pengcheng;Zhu, Junjie;Shehu, Amina I;Lu, Jie;Chen, Jing;Zhong, Xiao;Ma, Xiaochao
• 通讯作者: Ma, Xiaochao

The essential role of the transporter ABCG2 in the pathophysiology of erythropoietic protoporphyria.

转运蛋白 ABCG2 在红细胞生成性原卟啉症病理生理学中的重要作用。

• 发表时间: 2019
• 影响因子: 13.6
• 作者: Wang, Pengcheng;Sachar, Madhav;Lu, Jie;Shehu, Amina I;Zhu, Junjie;Chen, Jing;Liu, Ke;Anderson, Karl E;Xie, Wen;Gonzalez, Frank J;Klaassen, Curtis D;Ma, Xiaochao
• 通讯作者: Ma, Xiaochao