Developmental Aspects of Aminopenicillin Renal Clearance

氨基青霉素肾清除率的发展方面

• 批准号: 8677916
• 负责人: SANJAY K NIGAM
• 金额: $ 12.62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8677916
• 关键词: Active Biological Transport; Adolescent; Affect; Age; Amoxicillin; Ampicillin; Antiviral Agents; Best Pharmaceuticals for Children Act; Bioinformatics; Biological Models; California; Carrier Proteins; Characteristics; Child; Childhood; Ciprofloxacin; Citric Acid Cycle; Clinical; Clinical Trials; Code; Communicable Diseases; Complex; Data; Defect; Development; Diuretics; Dose; Drug Interactions; Drug Kinetics; Drug Transport; Excretory function; Face; Family; Genes; Genetic Polymorphism; Guidelines; Infant; Ketones; Kidney; Knock-out; Measures; Mediating; Metabolism; Modeling; Morphogenesis; Neonatal; Newborn Infant; Non-Steroidal Anti-Inflammatory Agents; Organic Anion Transporters; Pathway interactions; Pattern; Penicillins; Pharmaceutical Preparations; Pharmacology; Physiology; Play; Polyamines; Predictive Value; Premature Infant; Rattus; Regulation; Renal Tissue; Renal clearance function; Research; Research Personnel; Research Project Grants; Risk; Role; Route; Scientist; Specialized Center; Survival Rate; System; Testing; Universities; absorption; age group; antimicrobial; clinically relevant; early childhood; information model; member; metabolic abnormality assessment; metabolomics; model design; nephrogenesis; nephrotoxicity; patient population; pediatric pharmacology; pharmacokinetic model; postnatal; programs; response; small molecule; solute; transcriptomics; uptake; vitamin metabolism

This project, entitled "Developmental Aspects of Aminopenicillin Renal Clearance", is submitted as Research Project 3 of an application responsive to RFA-HD-10-026: Specialized Center in Research in Pediatric Developmental Pharmacology Program (U54). The overall theme of the proposed program at the University of California, San Diego, is to bring together non-clinical and clinical experts in the fields of developmental physiology, pharmacology, and infectious diseases to advance the field of pediatric developmental pharmacology. Project 3 achieves this purpose by bringing together Dr. Sanjay Nigam, a basic scientist with an expertise in renal morphogenesis and the discoverer of organic anion transporter (Oat) 1 critical to aminopenicillin excretion, and the expertise in pediatric pharmacokinetic modeling and pediatric clinical trials described in the overall proposal. The purpose of Project 3 is to the elucidate the age- and developmentally-related changes in the SLC22 family of solute carrier proteins in the kidney, which are critical in the handling and elimination of several commonly-used, yet potentially toxic drugs in children, including diuretics, antivirals, and antiretrovirals. Thus in the first part of the project, transcriptomic analysis will be undertaken to determine the pattern of expression for SLC22 transporters in the maturing kidney. Since these transport proteins also play an essential role In the handling and elimination of a wide variety of key metabolites, metabolite excretion will also be examined during postnatal and juvenile development. The first part of the project is aimed at the creation of a predictive systems model of the transcriptomic and metabolomic response of the renal SLC22 drug transporters during kidney maturation in neonatal and juvenile rats. Simultaneously, pharmacokinetic analysis of aminopenicillin in postnatal and juvenile rats will be undertaken to obtain provide important information about the renal clearance of aminopenicillins in neonatal development and the relationship between SLC22 substrates and aminopenicillin excretion. The model derived from the rat studies will be used to refine the pediatric PK model to establish a comprehensive renal transporter model designed to generate rational dosing guidelines.

该项目题为“氨基减少素肾脏清除的发育方面”，作为对RFA-HD-10-0-026的申请书3的研究3：小儿发展药理学计划（U54）的专业中心。加州大学圣地亚哥大学提议的计划的总体主题是将发育生理学，药理学和传染病领域的非临床和临床专家汇集在一起​​，以促进儿科领域 发展药理学。项目3通过将肾脏形态发生专业知识的基础科学家Sanjay Nigam博士汇总在一起来实现这一目的，并且有机阴离子转运蛋白转运蛋白（OAT）1对氨基减少蛋白的排泄至关重要，并且在整体上描述了儿童药物制作模型和儿童临床临床试验的专业知识。项目3的目的是阐明肾脏中SLC22溶质载体蛋白家族的年龄和发育相关的变化，这对于包括利尿剂，抗病毒药物和抗雷神病的儿童的处理和消除对儿童的处理和消除至关重要。因此，在项目的第一部分中，将进行转录组分析，以确定成熟肾脏中SLC22转运蛋白的表达模式。 由于这些转运蛋白在处理和消除各种关键代谢产物中也起着至关重要的作用，因此在产后和少年发育期间还将检查代谢物排泄。该项目的第一部分旨在创建转录组和 新生儿和少年大鼠肾脏成熟期间肾脏SLC22药物转运蛋白的代谢组反应。同时，将对产后和少年大鼠中氨基氨基霉素进行药代动力学分析，以获得有关新生儿发育中氨基元素清除率的重要信息，以及SLC22底物与氨基氨基霉素排泄物之间的关系。从大鼠研究中得出的模型将用于完善小儿PK模型，以建立旨在生成有理剂量指南的综合肾脏转运蛋白模型。