have a common mechanism of action but, because of their distinct structures, they exhibit somewhat different pharmacokinetic profiles. Some are administered as prodrugs that need to be converted to active metabolites (lovastatin, simvastatin), for some both the parent compound and the metabolites are active (atorvastatin, rosuvastatin), while for others, only the parent compound is active (fluvastatin, pravastatin). Atorvastatin, lovastatin and simvastatin are lipophilic and undergo extensive first-pass metabolism which lowers their bioavailability. Pravastatin and rosuvastatin are hydrophilic and need active transport to be taken up by the cells. Generally, it is assumed that statins undergo passive intestinal absorption and subsequently are taken up from the blood stream into the liver by members of solute carrier transporter family. Generally, it is assumed that statins undergo passive intestinal absorption and subsequently are taken up from the blood stream into the liver by members of solute carrier transporter family. Statin metabolism occurs primarily in the liver and to some extent, in the kidney. The liver is also the site for the pharmacodynamic action of statins as it is the organ of primary cholesterol biosynthesis. Genetic variation in the genes of statin metabolism and/or of lipid metabolism including cholesterol biosynthesis, may affect the pharmacokinetics and pharmacodynamics of the drug. Statins have also been reported to exhibit cholesterol-independent, 'pleiotropic' and beneficial effects. In addition, statins, which are generally well tolerated, have been associated with adverse effects. A small percentage of patients develop statin-related myopathy such as myalgia and rarely, fatal rhabdomyolysis. The mechanisms of these effects have not been determined, yet several remarks need be made. The enzymes that metabolize the statins also metabolize other drugs and this may impact on the overall statin concentration. Low cholesterol levels may affect membrane fluidity and excitability as well as increase the expression of LDL receptor and uptake of lipids. Finally, inhibition of the cholesterol biosynthesis at a step before the isoprenoid pathway splits into the sterol and the non-sterol arms can lead to decreased levels of compounds such as dolichol, ubiquinone or coenzyme Q10 and/or of prenylated proteins. Members of the small G proteins superfamily involved in cell growth and apoptosis need to be lipid-modified for proper cellular localization. [To access the PharmGKB diagram page click here]...(less)