Zebrafish Cytochrome P450 Assays for Assessing Drug Metabolism and Drug Safety

用于评估药物代谢和药物安全性的斑马鱼细胞色素 P450 测定

• 批准号: 7393512
• 负责人: Chunqi Li
• 金额: $ 16.07万
• 依托单位: PHYLONIX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393512
• 关键词: Adverse effects; Affect; Animal Model; Animals; Automation; Biological Assay; CYP3A4 gene; Cytochrome P450; Cytochromes; Detection; Dexamethasone; Dimethyl Sulfoxide; Dose; Drug Interactions; Enzymes; Evaluation; Family; Genetic; Genetic Transcription; Goals; Government; Hepatic; Hepatocyte; Human; In Situ Hybridization; Intestines; Lead; Life; Liver; Mammals; Measures; Messenger RNA; Metabolism; Modification; Oryctolagus cuniculus; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phenobarbital; Physiological; Proteins; Purpose; Rattus; Reaction; Reporting; Research; Rifampin; Safety; Screening procedure; System; Therapeutic Agents; Toxic effect; Treatment Efficacy; Zebrafish; base; clinically relevant; cytochrome P450 3A; drug metabolism; inhibitor/antagonist; member; preclinical study; response

DESCRIPTION (provided by applicant): Cytochrome P450 (CYP) enzymes catalyze the majority of known drug metabolism and the bulk of these reactions occur in the liver. As a consequence, many clinically relevant drug-drug interactions are associated with inhibition and/or induction of a specific CYP enzyme. Modifications of CYP activities can have profound effects on therapeutic efficacy and can lead to life-threatening toxicity. In order to provide an early warning system for potential serious side effects, detection of specific CYPs responsible for drug metabolism and drug-drug interactions is a goal of all pre-clinical studies. An ideal CYP assay should be rapid, robust, reliable, reproducible, and amenable to automation in multiwell plate formats. This research will develop a microplate format high throughput whole zebrafish CYP functional assay for assessing drug metabolism and drug safety. Based on genetic and physiological similarity to humans, zebrafish show promise as an efficient, predictive animal model for assessing drug metabolism and drug safety. The zebrafish assay will facilitate detection of specific cytochromes responsible for drug metabolism and drug-drug interactions, and provide an early warning system for potential serious side effects,

描述（由申请人提供）：细胞色素P450（CYP）酶催化大多数已知药物代谢，这些反应大部分发生在肝脏中。因此，许多临床相关的药物-药物相互作用与抑制和/或诱导特异性β-内酰胺酶有关。修饰抗肿瘤活性可能对治疗效果产生深远影响，并可能导致危及生命的毒性。为了提供潜在严重副作用的早期预警系统，检测负责药物代谢和药物-药物相互作用的特定CYP是所有临床前研究的目标。一个理想的荧光定量分析应该是快速的、稳健的、可靠的、可重复的，并且适合于多孔板形式的自动化。本研究将建立一种高通量的微板全斑马鱼代谢功能检测方法，用于评价药物代谢和药物安全性。基于与人类的遗传和生理相似性，斑马鱼显示出作为评估药物代谢和药物安全性的有效预测动物模型的前景。 斑马鱼检测将有助于检测负责药物代谢和药物相互作用的特定细胞色素，并为潜在的严重副作用提供早期预警系统，