Ribavirin depletes endogenous nucleotide pools

利巴韦林消耗内源核苷酸库

• 批准号: 8523852
• 负责人: JENNIFER JUSTICE KISER
• 金额: $ 7.96万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8523852
• 关键词: Address; Adenosine Triphosphate; Adverse effects; Anemia; Antiviral Agents; Biological Assay; Blood; Blood Cells; Cells; Chronic Hepatitis C; Cirrhosis; Clinic; Clinical; Clinical Trials; Coupled; Cytolysis; Dose; Dose-Limiting; Drug usage; Enrollment; Enzymes; Erythrocytes; Failure; Future; Genes; Genetic; Genotype; Grant; Guanosine Triphosphate; HIV; Health; Hemolytic Anemia; Hepatic; Hepatitis B; Hepatitis C virus; Hepatology; Human; Human Volunteers; Immune; Immunologics; In Vitro; Incidence; Investigation; Knowledge; Life; Light; Liquid Chromatography; Malignant Neoplasms; Measures; Mediating; Mononuclear; Nucleosides; Nucleotides; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Polymerase; Primary carcinoma of the liver cells; Purine Nucleotides; Purines; RNA Viruses; Regimen; Ribavirin; Role; Single Nucleotide Polymorphism; Technology; Therapeutic Effect; Toxic effect; Variant; Viral; Virus Diseases; Virus Replication; Work; analog; base; enzyme activity; improved; in vivo; inhibitor/antagonist; inosine triphosphatase; liquid chromatography mass spectrometry; nucleoside analog; peripheral blood; purine; response; tandem mass spectrometry; therapy development; treatment response; tripolyphosphate

DESCRIPTION (provided by applicant): Ribavirin, a nucleoside analog, is one of the only broad-spectrum antiviral drugs available in the world, and it is a fundamental component of treatment for chronic Hepatitis C virus (HCV). Despite decades of clinical use, the exact mechanisms by which ribavirin inhibits HCV replication and causes its major dose limiting toxicity, anemia are unclear. Our lack of understanding of how ribavirin works and causes anemia represent fundamental gaps in our knowledge of the treatment of HCV. To optimize HCV cure rates and minimize anemia from ribavirin-based treatment, we need to understand this drug's pharmacology. In vitro, ribavirin depletes endogenous purines which likely explains its toxic and therapeutic effects, but this has not been investigated in humans. Through this application, Dr. Kiser will extend efforts on her K23 and explore the effects of ribavirin on endogenous purines. The specific aims for the study are to (1) compare the change in endogenous purine concentrations in the red blood and peripheral blood mononuclear cells of HCV-infected patients on ribavirin-based treatment across ITPA activity phenotype groups and (2) to determine associations between endogenous purine depletion and virologic response and anemia and the degree to which ITPA activity phenotype moderates these effects. To address these aims, we will measure endogenous purine concentrations before starting ribavirin-based HCV treatment and 4- and 12-weeks after initiating treatment and ribavirin triphosphate concentrations 4- and 12-weeks after initiating treatment in the peripheral blood mononuclear and red blood cells of 40 subjects in Dr. Kiser's K23 study and 170 subjects prospectively enrolled (and stratified by ITPA activity phenotype) through our Hepatology clinic. This study will increase our understanding of how ribavirin inhibits HCV replication and causes anemia and determine if there are differences in effect based on ITPA genetics. Additionally, while the LC/MS/MS assay developed through this grant will be immediately used to address the aims of this application, the technology can also be applied to investigations of the effects of HCV nucleoside polymerase inhibitors and nucleos(t)ide analogs used in the treatment of HIV, Hepatitis B, and cancer on endogenous nucleotide pools.

说明(申请人提供)：利巴韦林是一种核苷类似物，是世界上仅有的广谱抗病毒药物之一，是治疗慢性丙型肝炎病毒(丙型肝炎病毒)的基本成分。尽管临床使用了几十年，但利巴韦林抑制丙型肝炎病毒复制并导致其主要剂量限制性毒性-贫血-的确切机制尚不清楚。我们对利巴韦林如何起作用和引起贫血缺乏了解，这是我们对丙型肝炎治疗知识的根本差距。为了优化丙型肝炎病毒的治愈率并最大限度地减少基于利巴韦林治疗的贫血，我们需要了解这种药物的药理。在体外，利巴韦林消耗内源性嘌呤，这可能解释了它的毒性和治疗作用，但这还没有在人类身上进行研究。通过这一应用，Kiser博士将在她的K23上继续努力，并探索利巴韦林对内源性嘌呤的影响。这项研究的具体目的是(1)比较基于利巴韦林治疗的丙型肝炎病毒感染者红细胞和外周血单核细胞中内源性嘌呤浓度在不同ITPA活性表型组之间的变化；(2)确定内源性嘌呤耗竭与病毒学反应和贫血之间的联系，以及ITPA活性表型对这些影响的缓和程度。为了实现这些目标，我们将在开始基于利巴韦林的丙型肝炎病毒治疗前以及开始治疗后4周和12周检测内源性嘌呤浓度，并在开始治疗4周和12周后检测Kiser博士的K23研究中的40名受试者和通过我们的肝科临床进行前瞻性纳入(并按ITPA活性表型进行分层)的170名受试者的外周血单核细胞和红细胞中的三磷酸利巴韦林浓度。这项研究将 增加我们对利巴韦林如何抑制丙型肝炎病毒复制和引起贫血的理解，并确定是否有基于ITPA遗传学的效果差异。此外，虽然通过这笔赠款开发的LC/MS/MS分析将立即用于解决这一应用的目的，但该技术也可以用于研究用于治疗艾滋病毒、乙肝和癌症的丙型肝炎病毒核苷聚合酶抑制剂和核苷酸(T)类似物对内源核苷酸池的影响。

项目成果

Drug-drug interactions during antiviral therapy for chronic hepatitis C.

• DOI: 10.1038/nrgastro.2013.106
• 发表时间: 2013-10
• 期刊: Nature reviews. Gastroenterology & hepatology
• 作者: Kiser JJ;Burton JR Jr;Everson GT
• 通讯作者: Everson GT

Serum and cellular ribavirin pharmacokinetic and concentration-effect analysis in HCV patients receiving sofosbuvir plus ribavirin.

接受索磷布韦联合利巴韦林的 HCV 患者的血清和细胞利巴韦林药代动力学和浓度效应分析。

• DOI: 10.1093/jac/dkv122
• 发表时间: 2015
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: Rower,JosephE;Meissner,EricG;Jimmerson,LeahC;Osinusi,Anu;Sims,Zayani;Petersen,Tess;Bushman,LaneR;Wolfe,Pamela;McHutchison,JohnG;Kottilil,Shyamasundaran;Kiser,JenniferJ
• 通讯作者: Kiser,JenniferJ