Statin Lactones in Statin Toxicity

他汀类药物毒性中的他汀类内酯

基本信息

  • 批准号:
    6557678
  • 负责人:
  • 金额:
    $ 33.91万
  • 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 2007-03-31
  • 项目状态:
    已结题

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.
性状(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指征,一般耐受性良好。然而,他汀类药物与主要降低血糖的贝特类药物(尤其是烟酸或吉非罗齐)或强效细胞色素P450/p-糖蛋白抑制剂联合使用可显著增加发生肌病(如潜在致死性横纹肌溶解症)的风险。最近一个强调他汀类药物/贝特类药物相互作用临床重要性的例子是,在西立伐他汀与贝特类药物吉非贝齐联合给药时,报告了至少40例致死性横纹肌溶解症病例后,于2001年8月8日将西立伐他汀撤出市场。虽然对于每种他汀类药物,体内存在酸和内酯形式之间的平衡,但很少有人关注他汀类药物内酯作为开放酸给药的潜在作用(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作用。似乎可以合理地假设,它们对细胞色素P450酶、转运蛋白的接近性和亲和力及其组织分布,例如进入肌肉细胞,与酸显著不同。我们假设他汀类内酯在他汀类药物的药代动力学和毒性中起关键作用。为了确定他汀类内酯在他汀类毒性中的作用,我们将使用磁共振波谱(MRS)评估内酯的药代动力学及其对肝脏和肌肉细胞代谢的药效学影响。这将是我们的主要目标,以评估他汀类药物的药代动力学,毒性和药物-药物相互作用的他汀类药物相比,其相应的酸的机制作用。我们的次要目标是比较不同他汀类药物的内酯/酸。

项目成果

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科研奖励数量(0)
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UWE CHRISTIANS其他文献

UWE CHRISTIANS的其他文献

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{{ 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:
    8198336
  • 财政年份:
    2011
  • 资助金额:
    $ 33.91万
  • 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:
    8303377
  • 财政年份:
    2011
  • 资助金额:
    $ 33.91万
  • 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:
    $ 33.91万
  • 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:
    $ 33.91万
  • 项目类别:
CORE--MASS SPECTOMETRY
核心——质谱
  • 批准号:
    7470674
  • 财政年份:
    2007
  • 资助金额:
    $ 33.91万
  • 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:
    $ 33.91万
  • 项目类别:
CORE--MASS SPECTOMETRY
核心——质谱
  • 批准号:
    7006531
  • 财政年份:
    2005
  • 资助金额:
    $ 33.91万
  • 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:
    $ 33.91万
  • 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:
    7031763
  • 财政年份:
    2003
  • 资助金额:
    $ 33.91万
  • 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:
    6896745
  • 财政年份:
    2003
  • 资助金额:
    $ 33.91万
  • 项目类别:

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