Implications of Hypothermia on Hepatic Drug Metabolism

低温对肝脏药物代谢的影响

基本信息

批准号：
7681466
负责人：
SAMUEL M POLOYAC
金额：
$ 24.94万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7681466
关键词：
Acute Affect Affinity Alfentanil American Heart Association Analytical Chemistry Anesthetics Animal Model Animals Attenuated Binding Blood flow CYP2E1 gene CYP3A4 gene Chronic Chronic Phase Clinical Clinical Research Clinical Trials Contusions Critical Care Critical Illness Cytochrome P450 Data Down-Regulation Drug Interactions Drug Kinetics Enzymes Failure Fentanyl Free Radicals Future Goals Heart Arrest Hepatic In Vitro Individual Injury Institutes Kidney Laboratories Lesion Liver Mediating Metabolism Metoprolol Modeling Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Plasma Plasma Proteins Protein Binding Protein Isoforms Rattus Regulation Regulatory Pathway Research Research Personnel Rewarming Safety System Techniques Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic Uses Time Tissues Trauma Traumatic Brain Injury Work base brain tissue clinically relevant cytochrome P-450 CYP2C subfamily cytokine design drug clearance drug metabolism in vivo induced hypothermia insight mRNA Expression natural hypothermia neuroprotection programs protein metabolism response standard of care transcription factor

项目摘要

DESCRIPTION (provided by applicant): Clinical use of systemic therapeutic hypothermia is being instituted nationally as standard of care for patients suffering a cardiac arrest (CA). Recent clinical trials have demonstrated the safety and neuroprotective benefits, thereby, prompting the American Heart Association to designate systemic hypothermia as a level one therapy in CA patients. In addition, hypothermia provides neuroprotective benefits after traumatic brain injury (TBI). Patients who suffer a CA or TBI receive a wide array of drugs that depend on hepatic metabolism by the cytochrome P450 (CYP450) enzyme system. In fact, several studies have demonstrated that hypothermia increases the plasma concentrations of hepatically eliminated drugs. Despite the increased clinical implementation and the potential for therapy-drug interaction, a paucity of data exists concerning the effects of therapeutic hypothermia on CYP450-mediated drug clearance. The hypotheses of this proposal are that: 1) Mild and moderate hypothermia differentially affect the in vitro functional activity and regulation of the 7 major CYP450 isoforms in rat CA and TBI models. 2) Mild to moderate hypothermia produce alterations in hepatic blood flow, intrinsic enzyme clearance, and plasma protein binding in rat CA and TBI models. 3) Mild and moderate hypothermia alters the disposition of therapeutic agents in vivo in rat CA and TBI models, thereby, affecting the full neuroprotective benefits of therapeutic hypothermia. This project will utilize combinations of in vivo pharmacokinetic assessments, in vitro functional regulation analyses, and analytical chemistry techniques in models of CA and TBI under normothermic (37 degrees), mild hypothermic (33 degrees), and moderately hypothermic (30 degrees) conditions. In addition, this research will lend insight into the cellular mechanisms that produce both acute and chronic changes in CYP450 function. The results of this research are necessary to determine: 1) The implications of hypothermic therapy after traumatic insult on the disposition of drugs that depend on hepatic elimination; 2) The in vivo mechanism(s) by which hypothermia and trauma alter hepatic drug elimination, and; 3) The effect of hypothermia and trauma on the cellular mechanisms and functional regulation of CYP450 isoform expression. Once completed, this research will provide critical information to design future clinical studies to optimize the benefits of this breakthrough therapy.

描述（由申请人提供）：在全国范围内为患有心脏骤停的患者（CA）的患者建立了全国治疗性体温过低的临床使用。最近的临床试验证明了安全性和神经保护作用，因此促使美国心脏协会将系统性体温过低指定为CA患者的一级疗法。此外，体温过低提供神经保护益处（TBI）。患有CA或TBI的患者会接受各种依赖细胞色素P450（CYP450）酶系统的药物。实际上，几项研究表明，体温过低会增加肝脏消除药物的血浆浓度。尽管临床实施增加和治疗 - 药物相互作用的潜力，但对于治疗性体温过低对CYP450介导的药物清除率的影响仍然存在数据。该提议的假设是：1）在大鼠CA和TBI模型中，温和和中度的体温过低会差异地影响7个主要CYP450同工型的体外功能活性和调节。 2）轻度至中度的体温过低会在大鼠CA和TBI模型中产生肝血流，内在酶清除率和血浆蛋白结合的改变。 3）温和和中度的低温改变了治疗剂在大鼠和TBI模型中体内的处理，从而影响了治疗性低温的全部神经保护益处。该项目将利用体内药代动力学评估，体外功能调节分析和分析化学技术的组合，在正常热（37度），轻度低温（33度）和中等温度（中等温度（30度）条件下，CA和TBI模型中的分析化学技术。此外，这项研究将深入了解CYP450功能中急性和慢性变化的细胞机制。这项研究的结果是确定：1）创伤性侮辱对依赖肝脏消除的药物的处置后的低温治疗的影响； 2）体内机制通过体温过低和创伤改变了肝药物的消除，并且； 3）体温过低和创伤对CYP450同工型表达的细胞机制和功能调节的影响。完成后，这项研究将为设计未来的临床研究提供关键信息，以优化这种突破疗法的好处。