Discovery and development of statins trials showed very good inhibitory effect as in clinical trials, however in a long term toxicity study in dogs it resulted in toxic effects at higher doses and as a result was believed to be too toxic to be given to humans. In 1978, Alfred Alberts and colleagues at Merck Research Laboratories discovered a new natural product in a fermentation broth of "Aspergillus terreus", their product showed good HMGR inhibition and they named the product mevinolin, which later became known as lovastatin. The cholesterol controversy began in the early promotion of statins. Statins are a competitive antagonists of HMG CoA,
Discovery and development of statins lipophilic and also had the largest percentage of serious adverse effects due to its ability to inhibit vascular smooth muscle proliferation and as a result was voluntarily removed from the market by the manufacturer. All statins are (metabolized) by the liver, which causes their low systemic bioavailability. Lovastatin and simvastatin are administered in their lactone forms, which is more lipophilic than their free acid forms, and therefore they have to be activated by hydrolysis to the active anionic carboxylate form. Cytochrome P450(CYP) isoenzymes are involved in the oxidative metabolism of the statins, with CYP3A4 and CYP2C9 isoenzymes being the most