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.

摘要 本申请的目的是确定本发明化合物的肝毒性机制。 现有的药物增强剂，并提供一个基于机制的指导下一个开发 产生具有较小肝毒性的药物增强剂。利托那韦（RTV）和cobicistat（COBI）是 第一代和第二代药物增强剂。RTV被认为是一种肝毒素， 机制仍然难以捉摸。在最近的一系列临床试验中，研究了RTV的肝毒性。 在用利福平（RIF）或依法韦仑（EFV）预治疗的受试者中显著增强。两 RIF和EFV是人黑色素X受体（PXR）的有效配体，PXR是一种配体依赖性转录因子， 在药物代谢中上调细胞色素P450 3A 4（CYP 3A 4）的因子。由于国际- 种属间配体依赖性PXR激活的差异，我们建立了双转基因小鼠模型， 表达人PXR和CYP 3A 4（TgCYP 3A 4/hPXR）。通过使用TgCYP 3A 4/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 造成的肝损伤与RTV相似。此外，我们的代谢组学分析表明，RTV和COBI 经历相同的生物活化途径以产生毒性代谢物，其由CYP 3A 4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CYP 3A 4介导的RTV/COBI生物活化。我们还假设， 绕过RTV和COBI的生物活化途径将减轻其肝毒性。来测试我们 假设，我们提出了以下三个具体目标：（1）确定人类PXR的作用， （2）确定人CYP 3A 4在RTV/COBI肝毒性中的作用;和 (3)探索新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.

• DOI: 10.1016/j.bcp.2017.09.001
• 发表时间: 2017-12-01
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Wang P;Shehu AI;Lu J;Joshi RH;Venkataramanan R;Sugamori KS;Grant DM;Zhong XB;Ma X
• 通讯作者: Ma X

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury.

• DOI: 10.1007/s40495-018-0131-8
• 发表时间: 2018-06
• 期刊: Current pharmacology reports
• 作者: Bao Y;Ma X;Rasmussen TP;Zhong XB
• 通讯作者: Zhong XB

CYP1A1 and 1B1-mediated metabolic pathways of dolutegravir, an HIV integrase inhibitor.

• DOI: 10.1016/j.bcp.2018.10.012
• 发表时间: 2018-12
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Zhu J;Wang P;Li F;Lu J;Shehu AI;Xie W;McMahon D;Ma X
• 通讯作者: Ma X

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。

• DOI: 10.1021/acs.chemrestox.9b00098
• 发表时间: 2019
• 期刊: Chemical research in toxicology
• 影响因子: 4.1
• 作者: Wang,Pengcheng;Zhu,Junjie;Shehu,AminaI;Lu,Jie;Chen,Jing;Zhong,Xiao-Bo;Ma,Xiaochao
• 通讯作者: Ma,Xiaochao

Role of CYP2A6 in Methimazole Bioactivation and Hepatotoxicity.

• DOI: 10.1021/acs.chemrestox.1c00300
• 发表时间: 2021-12-20
• 期刊: Chemical research in toxicology
• 影响因子: 4.1
• 作者: Li J;Hussain Z;Zhu J;Lei S;Lu J;Ma X
• 通讯作者: Ma X