The Role of Statin Lactones in Statin Toxicity

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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.