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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071805-04
Application #
7031763
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Srinivas, Pothur R
Project Start
2003-04-08
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$334,288
Indirect Cost
Name
University of Colorado Denver
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Klawitter, Jelena; Shokati, Touraj; Moll, Vanessa et al. (2010) Effects of lovastatin on breast cancer cells: a proteo-metabonomic study. Breast Cancer Res 12:R16
Klawitter, Jost; Schmitz, Volker; Klawitter, Jelena et al. (2007) Development and validation of an assay for the quantification of 11 nucleotides using LC/LC-electrospray ionization-MS. Anal Biochem 365:230-9
Laudi, Sven; Trump, Saskia; Schmitz, Volker et al. (2007) Serotonin transporter protein in pulmonary hypertensive rats treated with atorvastatin. Am J Physiol Lung Cell Mol Physiol 293:L630-8
Haschke, Manuel; Zhang, Yan Ling; Kahle, Christine et al. (2007) HPLC-atmospheric pressure chemical ionization MS/MS for quantification of 15-F2t-isoprostane in human urine and plasma. Clin Chem 53:489-97
Christians, Uwe; Schmitz, Volker; Haschke, Manuel (2005) Functional interactions between P-glycoprotein and CYP3A in drug metabolism. Expert Opin Drug Metab Toxicol 1:641-54
Christians, Uwe (2004) Transport proteins and intestinal metabolism: P-glycoprotein and cytochrome P4503A. Ther Drug Monit 26:104-6
Serkova, Natalie J; Christians, Uwe; Benet, Leslie Z (2004) Biochemical mechanisms of cyclosporine neurotoxicity. Mol Interv 4:97-107