Cardiovascular diseases are among society’s major public health problems as they are the most common cause of death in the developed world as well as in the developing countries. Data suggest that cardiovascular mortality is declining, but remains a key health burden for all developed societies. One of the main risk factors for cardiovascular diseases is elevated cholesterol, which is also called the "silent killer", because patients are often unaware of it, but if left untreated it can cause very serious illnesses. When non-pharmacological approaches are no longer sufficient, treatment with medicaments is a must and not merely a recommendation. Statins are a class of lipid-lowering drugs, which have shown significant advances in the prevention of risk of atherosclerosis and its complications. Simvastatin is a statin class drug whose bioavailability is very limited by extensive first-pass hepatic metabolism. Two prodrugs of simvastatin for lymphatic absorption were synthesized for the purpose of our master’s thesis. Lymphatic absorption can avoid the first-pass hepatic metabolism and as a consequence, the bioavailability of drugs is higher. The simvastatin prodrugs are glyceride mimetics, which are supposed to mimic the digestion, re-esterification, and lymphatic transport pathways of dietary triglycerides. The glyceride mimetics would then combine with lipoproteins and, instead of being absorbed into the portal blood, they would be absorbed into the lymph. For the purpose of our master’s thesis we first optimized the synthesis of glycerol 1,3-distearate, using three different synthetic routes: the synthesis of glycerol 1,3-distearate from 1,3-dihydroxyacetone dimer, from solketal, and directly from glycerol. We found that the most optimal synthesis of glycerol 1,3-distearate is directly from glycerol. Then, the appropriate spacer from glutaric and succinic acids was bound to the glycerol 1,3-distearate. The final prodrugs were synthesized by binding simvastatin and glycerol 1,3-distearate with the appropriate spacer. Both prodrugs were evaluated for the release of simvastatin from the prodrug. We found that both prodrugs are metabolized by liver microsomal enzymes. After 15 minutes, 1.07% of simvastatin is released from the prodrug with a glutarate spacer, 1.02% is released after 30 minutes, 1.92% is released after 60 minutes, and after 120 minutes, 2.60% of simvastatin is released, while 2.36 % of simvastatin is released from a prodrug with a succinate spacer after 15 minutes, 4.13% after 30 minutes, 5.15% after 60 minutes, and 6.30% of simvastatin after 120 minutes.
The results show that more simvastatin is released from a prodrug with a succinate spacer, so we can conclude that type of spacer affects the release of simvastatin.
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