利用人体肝脏组织芯片进行罪犯和受害者药物代谢酶诱导研究

IF 4.4 3区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Metabolism and Disposition Pub Date : 2024-10-07 DOI:10.1124/dmd.124.001497
Shivam Ohri, Paarth Parekh, Lauren Nichols, Shiny Amala Priya Rajan, Murat Cirit
{"title":"利用人体肝脏组织芯片进行罪犯和受害者药物代谢酶诱导研究","authors":"Shivam Ohri, Paarth Parekh, Lauren Nichols, Shiny Amala Priya Rajan, Murat Cirit","doi":"10.1124/dmd.124.001497","DOIUrl":null,"url":null,"abstract":"<p><p>Polypharmacy-related drug-drug interactions (DDIs) are a significant and growing healthcare concern. An increasing number of therapeutic drugs on the market underscores the necessity to accurately assess new drug combinations during pre-clinical evaluation for DDIs. <i>In vitro</i> primary human hepatocytes (PHH) models are only applicable for short term induction studies due to their rapid loss of metabolic function. Though co-culturing non-human stromal cells with PHH has been shown to stabilize metabolic activity long-term, there are concerns about human specificity for accurate clinical assessment. In this study, we demonstrate a PHH-only liver microphysiological system (MPS) in the Liver Tissue Chip (LTC) is capable of maintaining long-term functional and metabolic activity of PHH from three individual donors, and thus a suitable platform for long-term DDI induction studies. The responses to rifampicin induction of three PHH donors were assessed using CYP activity and mRNA changes. Additionally, victim PK studies were conducted with midazolam (high clearance) and alprazolam (low clearance) following perpetrator drug treatment, rifampicin-mediated induction, which resulted in a 2-fold and a 2.6-fold increase in midazolam and alprazolam intrinsic clearance values respectively compared to the untreated liver MPS. We also investigated the induction effects of different dosing regimens of the perpetrator drug (rifampicin) on CYP activity levels, showing minimal variation in the intrinsic clearance of the victim drug (midazolam). This study illustrates the utility of the LTC for <i>in vitro</i> liver-specific DDI induction studies, providing a translational experimental system to predict clinical clearance values of both perpetrator and victim drugs. <b>Significance Statement</b> This study demonstrates the utility of the Liver Tissue Chip (LTC) with primary human hepatocyte (PHH)-only liver microphysiological system (MPS) for drug-drug interaction (DDI) induction studies. This unique <i>in vitro</i> system with continuous recirculation maintains long-term functionality and metabolic activity for up to 4 weeks, enabling the study of perpetrator and victim drug pharmacokinetics, quantification of drug-induced CYP mRNA and activity levels, investigation of patient variability, and ultimately clinical predictions.</p>","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":" ","pages":""},"PeriodicalIF":4.4000,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"<b>Utilization of a Human Liver Tissue Chip for Drug-Metabolizing Enzyme Induction Studies of Perpetrator and Victim Drugs</b>.\",\"authors\":\"Shivam Ohri, Paarth Parekh, Lauren Nichols, Shiny Amala Priya Rajan, Murat Cirit\",\"doi\":\"10.1124/dmd.124.001497\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Polypharmacy-related drug-drug interactions (DDIs) are a significant and growing healthcare concern. An increasing number of therapeutic drugs on the market underscores the necessity to accurately assess new drug combinations during pre-clinical evaluation for DDIs. <i>In vitro</i> primary human hepatocytes (PHH) models are only applicable for short term induction studies due to their rapid loss of metabolic function. Though co-culturing non-human stromal cells with PHH has been shown to stabilize metabolic activity long-term, there are concerns about human specificity for accurate clinical assessment. In this study, we demonstrate a PHH-only liver microphysiological system (MPS) in the Liver Tissue Chip (LTC) is capable of maintaining long-term functional and metabolic activity of PHH from three individual donors, and thus a suitable platform for long-term DDI induction studies. The responses to rifampicin induction of three PHH donors were assessed using CYP activity and mRNA changes. Additionally, victim PK studies were conducted with midazolam (high clearance) and alprazolam (low clearance) following perpetrator drug treatment, rifampicin-mediated induction, which resulted in a 2-fold and a 2.6-fold increase in midazolam and alprazolam intrinsic clearance values respectively compared to the untreated liver MPS. We also investigated the induction effects of different dosing regimens of the perpetrator drug (rifampicin) on CYP activity levels, showing minimal variation in the intrinsic clearance of the victim drug (midazolam). This study illustrates the utility of the LTC for <i>in vitro</i> liver-specific DDI induction studies, providing a translational experimental system to predict clinical clearance values of both perpetrator and victim drugs. <b>Significance Statement</b> This study demonstrates the utility of the Liver Tissue Chip (LTC) with primary human hepatocyte (PHH)-only liver microphysiological system (MPS) for drug-drug interaction (DDI) induction studies. This unique <i>in vitro</i> system with continuous recirculation maintains long-term functionality and metabolic activity for up to 4 weeks, enabling the study of perpetrator and victim drug pharmacokinetics, quantification of drug-induced CYP mRNA and activity levels, investigation of patient variability, and ultimately clinical predictions.</p>\",\"PeriodicalId\":11309,\"journal\":{\"name\":\"Drug Metabolism and Disposition\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2024-10-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug Metabolism and Disposition\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1124/dmd.124.001497\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Metabolism and Disposition","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1124/dmd.124.001497","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

摘要

多药相关的药物相互作用(DDIs)是医疗保健领域日益严重的问题。市场上的治疗药物越来越多,这凸显了在临床前评估期间准确评估新药组合的 DDIs 的必要性。体外原代人类肝细胞(PHH)模型由于代谢功能丧失迅速,仅适用于短期诱导研究。虽然非人类基质细胞与 PHH 的共培养已被证明能长期稳定代谢活动,但在进行准确的临床评估时,人类的特异性仍令人担忧。在这项研究中,我们证明了肝组织芯片(LTC)中的纯PHH肝脏微生理系统(MPS)能够长期保持来自三个供体的PHH的功能和代谢活性,因此是进行长期DDI诱导研究的合适平台。我们利用 CYP 活性和 mRNA 变化评估了三个 PHH 供体对利福平诱导的反应。此外,我们还对肇事者药物治疗后的咪达唑仑(高清除率)和阿普唑仑(低清除率)进行了受害者 PK 研究,利福平介导的诱导使咪达唑仑和阿普唑仑的内在清除率值分别比未经处理的肝脏 MPS 增加了 2 倍和 2.6 倍。我们还研究了不同剂量方案的肇事药物(利福平)对 CYP 活性水平的诱导效应,结果显示受害药物(咪达唑仑)的内在清除率变化极小。本研究说明了 LTC 在体外肝脏特异性 DDI 诱导研究中的实用性,为预测加害药和受害药的临床清除率值提供了一个转化实验系统。意义声明 本研究证明了肝组织芯片(LTC)与仅有原代人类肝细胞(PHH)的肝脏微生理系统(MPS)在药物-药物相互作用(DDI)诱导研究中的实用性。这种独特的体外系统具有持续再循环功能,可长期保持功能和代谢活性长达 4 周,从而能够研究肇事者和受害者的药物药代动力学、量化药物诱导的 CYP mRNA 和活性水平、调查患者的变异性并最终进行临床预测。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Utilization of a Human Liver Tissue Chip for Drug-Metabolizing Enzyme Induction Studies of Perpetrator and Victim Drugs.

Polypharmacy-related drug-drug interactions (DDIs) are a significant and growing healthcare concern. An increasing number of therapeutic drugs on the market underscores the necessity to accurately assess new drug combinations during pre-clinical evaluation for DDIs. In vitro primary human hepatocytes (PHH) models are only applicable for short term induction studies due to their rapid loss of metabolic function. Though co-culturing non-human stromal cells with PHH has been shown to stabilize metabolic activity long-term, there are concerns about human specificity for accurate clinical assessment. In this study, we demonstrate a PHH-only liver microphysiological system (MPS) in the Liver Tissue Chip (LTC) is capable of maintaining long-term functional and metabolic activity of PHH from three individual donors, and thus a suitable platform for long-term DDI induction studies. The responses to rifampicin induction of three PHH donors were assessed using CYP activity and mRNA changes. Additionally, victim PK studies were conducted with midazolam (high clearance) and alprazolam (low clearance) following perpetrator drug treatment, rifampicin-mediated induction, which resulted in a 2-fold and a 2.6-fold increase in midazolam and alprazolam intrinsic clearance values respectively compared to the untreated liver MPS. We also investigated the induction effects of different dosing regimens of the perpetrator drug (rifampicin) on CYP activity levels, showing minimal variation in the intrinsic clearance of the victim drug (midazolam). This study illustrates the utility of the LTC for in vitro liver-specific DDI induction studies, providing a translational experimental system to predict clinical clearance values of both perpetrator and victim drugs. Significance Statement This study demonstrates the utility of the Liver Tissue Chip (LTC) with primary human hepatocyte (PHH)-only liver microphysiological system (MPS) for drug-drug interaction (DDI) induction studies. This unique in vitro system with continuous recirculation maintains long-term functionality and metabolic activity for up to 4 weeks, enabling the study of perpetrator and victim drug pharmacokinetics, quantification of drug-induced CYP mRNA and activity levels, investigation of patient variability, and ultimately clinical predictions.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
6.50
自引率
12.80%
发文量
128
审稿时长
3 months
期刊介绍: An important reference for all pharmacology and toxicology departments, DMD is also a valuable resource for medicinal chemists involved in drug design and biochemists with an interest in drug metabolism, expression of drug metabolizing enzymes, and regulation of drug metabolizing enzyme gene expression. Articles provide experimental results from in vitro and in vivo systems that bring you significant and original information on metabolism and disposition of endogenous and exogenous compounds, including pharmacologic agents and environmental chemicals.
期刊最新文献
Absorption, Distribution, Metabolism, and Excretion of Icenticaftor (QBW251) in Healthy Male Volunteers at Steady State and In Vitro Phenotyping of Major Metabolites. Differential Selectivity of Human and Mouse ABCC4/Abcc4 for Arsenic Metabolites. CYP P450 and non-CYP P450 Drug Metabolizing Enzyme Families Exhibit Differential Sensitivities towards Proinflammatory Cytokine Modulation. Quantitative Prediction of Drug-Drug Interactions Caused by CYP3A Induction Using Endogenous Biomarker 4β-Hydroxycholesterol. Utility of Common In Vitro Systems for Predicting Circulating Metabolites.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1