The Role of Statin Lactones in Statin Toxicity

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指数，通常耐受性良好。然而，他汀类药物与主要降低甘油三酯的贝特类药物（尤其是烟酸或吉非齐尔）或强效细胞色素P450/p-糖蛋白抑制剂联合使用可显著增加肌病的发生风险，如可能致命的横纹肌溶解。最近一个强调他汀/贝特药物相互作用的临床重要性的例子是，2001年8月8日，在报告了至少40例死亡的横纹肌溶解病例后，cerivastatin从市场上被下架，当时cerivastatin与贝特genfibrozil联合使用。尽管每种他汀类药物在体内都存在酸和内酯形式的平衡，但很少有人关注他汀类药物内酯作为开放酸（阿托伐他汀、西伐他汀、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，因为内酯形式比酸形式亲脂性强得多，并且似乎可以合理地假设它们对细胞色素P450酶、转运体及其组织分布（例如进入肌肉细胞）的接近和亲和力与酸有很大不同。我们的假设是他汀类内酯在他汀类药物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。我们的主要目标是评估他汀类内酯在他汀类药物的药代动力学、毒性和药物-药物相互作用中的机制作用，并将其与相应的酸进行比较。我们的第二个目标是比较不同的他汀类药物的内酯/酸。

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.