The Role of Statin Lactones in Statin Toxicity
他汀类药物内酯在他汀类药物毒性中的作用
基本信息
- 批准号:7031763
- 负责人:
- 金额:$ 33.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-04-08 至 2008-03-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have emerged as the most valuable cholesterol-lowering drugs. Statins have wide therapeutic indeces and are generally well tolerated. However, the combination of statins with mainly triglyceride-lowering fibrates, especially nicotinic acid or gemfibrozil, or potent cytochrome P450/p-glycoprotein inhibitors significantly increases the risk to develop myopathy such as potentially fatal rhabdomyolysis. A recent example stressing the clinical importance of statin/fibrate drug interactions is the removal of cerivastatin from the market on August 8, 2001 after at least 40 fatal cases of rhabdomyolysis were reported when cerivastatin was co-administered with the fibrate gemfibrozil. Although for each statin an equilibrium between both acid and lactone form exists in vivo, very little attention has been paid to the potential role of the lactones of statins administered as open acids (atorvastatin, cerivastatin, fluvastatin, pravastatin) in pharmacokinetic and pharmacodynamic drug interactions and toxicity.This is surprising since the lactone forms are considerably more lipophilic than the acid forms, and it seems reasonable to assume that their access and affinities to cytochrome P450 enzymes, transporters and their tissue distribution, e.g. into muscle cells, differs significantly from the acids. It is our hypothesis that the statin lactones play a key role in statin pharmacokinetics and toxicity. To identify the role of statin lactones in statin toxicity, we will assess both lactone pharmacokinetics and their pharmacodynamic effects on liver and muscle cell metabolism using magnetic resonance spectroscopy (MRS). It will be our primary goal to assess the mechanistic role of statin lactones in the pharmacokinetics, toxicity and drug-drug interactions of statins in comparison to their corresponding acids. Our secondary goal will be to compare the lactones/acids of the different statins with each other.
描述(由申请人提供):3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂(他汀类药物)已成为最有价值的降胆固醇药物。他汀类药物具有广泛的治疗效果并且通常具有良好的耐受性。然而,他汀类药物与主要降低甘油三酯的贝特类药物(尤其是烟酸或吉非贝齐)或强效细胞色素 P450/p-糖蛋白抑制剂的组合会显着增加发生肌病的风险,例如可能致命的横纹肌溶解症。最近的一个例子强调了他汀类药物/贝特类药物相互作用的临床重要性,即西立伐他汀与贝特类吉非贝齐联合用药时,报告了至少 40 例致命的横纹肌溶解症病例,并于 2001 年 8 月 8 日将西立伐他汀从市场上撤下。尽管对于每种他汀类药物,体内存在酸和内酯形式之间的平衡,但很少有人关注以开放酸形式施用的他汀类药物的内酯(阿托伐他汀、西立伐他汀、氟伐他汀、普伐他汀)在药代动力学和药效学药物相互作用和毒性中的潜在作用。这是令人惊讶的,因为内酯形式比内酯形式更亲脂。 酸形式,并且似乎可以合理地假设它们对细胞色素 P450 酶、转运蛋白及其组织分布的访问和亲和力,例如进入肌肉细胞,与酸显着不同。我们的假设是他汀类药物内酯在他汀类药物的药代动力学和毒性中起关键作用。为了确定他汀类药物内酯在他汀类药物毒性中的作用,我们将使用磁共振波谱 (MRS) 评估内酯药代动力学及其对肝脏和肌肉细胞代谢的药效学影响。我们的主要目标是评估他汀类内酯与其相应酸相比在他汀类药物的药代动力学、毒性和药物相互作用中的机制作用。我们的第二个目标是比较不同他汀类药物的内酯/酸。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Biochemical mechanisms of cyclosporine neurotoxicity.
环孢菌素神经毒性的生化机制。
- DOI:10.1124/mi.4.2.7
- 发表时间:2004
- 期刊:
- 影响因子:0
- 作者:Serkova,NatalieJ;Christians,Uwe;Benet,LeslieZ
- 通讯作者:Benet,LeslieZ
Effects of lovastatin on breast cancer cells: a proteo-metabonomic study.
洛伐他汀对乳腺癌细胞的影响:一项蛋白质代谢研究。
- DOI:10.1186/bcr2485
- 发表时间:2010
- 期刊:
- 影响因子:7.4
- 作者:Klawitter, Jelena;Shokati, Touraj;Moll, Vanessa;Christians, Uwe;Klawitter, Jost
- 通讯作者:Klawitter, Jost
Functional interactions between P-glycoprotein and CYP3A in drug metabolism.
- DOI:10.1517/17425255.1.4.641
- 发表时间:2005-12-01
- 期刊:
- 影响因子:4.3
- 作者:Christians, Uwe;Schmitz, Volker;Haschke, Manuel
- 通讯作者:Haschke, Manuel
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
UWE CHRISTIANS其他文献
UWE CHRISTIANS的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('UWE CHRISTIANS', 18)}}的其他基金
In Vivo Assessment of Calcineurin Inhibitor Toxicity in Children
儿童钙调神经磷酸酶抑制剂毒性的体内评估
- 批准号:
8303377 - 财政年份:2011
- 资助金额:
$ 33.43万 - 项目类别:
In Vivo Assessment of Calcineurin Inhibitor Toxicity in Children
儿童钙调神经磷酸酶抑制剂毒性的体内评估
- 批准号:
8198336 - 财政年份:2011
- 资助金额:
$ 33.43万 - 项目类别:
In Vivo Assessment of Calcineurin Inhibitor Toxicity in Children
儿童钙调神经磷酸酶抑制剂毒性的体内评估
- 批准号:
8460944 - 财政年份:2011
- 资助金额:
$ 33.43万 - 项目类别:
In Vivo Assessment of Calcineurin Inhibitor Toxicity in Children
儿童钙调神经磷酸酶抑制剂毒性的体内评估
- 批准号:
8660315 - 财政年份:2011
- 资助金额:
$ 33.43万 - 项目类别:
PHARMACOKIN&PHARMACODYN INTERACTION OF CORTICOSTEROIDS W/CYCLOSPORINE IN VLNTRS
医药金
- 批准号:
7377815 - 财政年份:2006
- 资助金额:
$ 33.43万 - 项目类别:
Effects of Immunosuppressants on Cell Metabolism
免疫抑制剂对细胞代谢的影响
- 批准号:
6772392 - 财政年份:2003
- 资助金额:
$ 33.43万 - 项目类别:
The Role of Statin Lactones in Statin Toxicity
他汀类药物内酯在他汀类药物毒性中的作用
- 批准号:
6732642 - 财政年份:2003
- 资助金额:
$ 33.43万 - 项目类别:
相似海外基金
Biophysics of biological transport and signaling "nanomachines": from theory to applications
生物运输和信号传导“纳米机器”的生物物理学:从理论到应用
- 批准号:
RGPIN-2022-04909 - 财政年份:2022
- 资助金额:
$ 33.43万 - 项目类别:
Discovery Grants Program - Individual
Investigation on water mass and biological transport in the Antarctic coastal areas through the oceanographic survey by penguins
通过企鹅海洋学调查研究南极沿海地区的水团和生物运输
- 批准号:
22H03737 - 财政年份:2022
- 资助金额:
$ 33.43万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Understanding mechanisms of biological transport and signaling for nanotechnology applications.
了解纳米技术应用的生物运输和信号传导机制。
- 批准号:
RGPIN-2016-06591 - 财政年份:2021
- 资助金额:
$ 33.43万 - 项目类别:
Discovery Grants Program - Individual
Understanding mechanisms of biological transport and signaling for nanotechnology applications.
了解纳米技术应用的生物运输和信号传导机制。
- 批准号:
RGPIN-2016-06591 - 财政年份:2020
- 资助金额:
$ 33.43万 - 项目类别:
Discovery Grants Program - Individual
Understanding mechanisms of biological transport and signaling for nanotechnology applications.
了解纳米技术应用的生物运输和信号传导机制。
- 批准号:
RGPIN-2016-06591 - 财政年份:2019
- 资助金额:
$ 33.43万 - 项目类别:
Discovery Grants Program - Individual
Understanding mechanisms of biological transport and signaling for nanotechnology applications.
了解纳米技术应用的生物运输和信号传导机制。
- 批准号:
RGPIN-2016-06591 - 财政年份:2018
- 资助金额:
$ 33.43万 - 项目类别:
Discovery Grants Program - Individual
Understanding mechanisms of biological transport and signaling for nanotechnology applications.
了解纳米技术应用的生物运输和信号传导机制。
- 批准号:
RGPIN-2016-06591 - 财政年份:2017
- 资助金额:
$ 33.43万 - 项目类别:
Discovery Grants Program - Individual
Understanding mechanisms of biological transport and signaling for nanotechnology applications.
了解纳米技术应用的生物运输和信号传导机制。
- 批准号:
RGPIN-2016-06591 - 财政年份:2016
- 资助金额:
$ 33.43万 - 项目类别:
Discovery Grants Program - Individual
Understanding the mechanisms of biological transport and signaling for nanotechnology applications
了解纳米技术应用的生物运输和信号传导机制
- 批准号:
402591-2011 - 财政年份:2015
- 资助金额:
$ 33.43万 - 项目类别:
Discovery Grants Program - Individual
Understanding the mechanisms of biological transport and signaling for nanotechnology applications
了解纳米技术应用的生物运输和信号传导机制
- 批准号:
402591-2011 - 财政年份:2014
- 资助金额:
$ 33.43万 - 项目类别:
Discovery Grants Program - Individual