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 that include SLCO1B1, SLCO1B3, SLCO2B1. Statins are metabolized by phase I and II enzymes and eliminated via efflux transporters mediated biliary excretion. Phase I enzymes are members of the cytochrome P450 superfamily; families 1 to 3 that have low substrate specificity and have not been well preserved during evolution, are responsible for the metabolism of most drugs and xenobiotics. Enzymes involved in phase I statin metabolism include CYP3A4, CYP2C8, CYP2C9, CYP2D6). Phase II enzymes carry out the conjugation of metabolites produced by phase I enzymes to render them prone for excretion. Glucoronidation of statin metabolites is carried out by members of the glucoronosyltranferase family including UGT1A1 and 3. Elimination of statins is carried out by members of the efflux family transporters ABCB1, ABCC2, ABCG2 or ABCB11. Statin metabolism and elimination takes place primarily in the liver and to a lesser 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. The lowering of cholesterol levels resulting from the action of statins has beneficial effect in the prevention of cardiovascular diseases. 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. Because the enzymes involved in statin metabolism are distinct members of families and some are only present in humans, the human genes are shown unless there is specific information for the rat ortholog. To see the ontology report for annotations, GViewer and download click here
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