Problem 1: The statins are a family of drugs used to lower serum cholesterol as a means of reducing the risk for cardiov

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Problem 1 The Statins Are A Family Of Drugs Used To Lower Serum Cholesterol As A Means Of Reducing The Risk For Cardiov 1 (76.1 KiB) Viewed 32 times

Problem 1: The statins are a family of drugs used to lower serum cholesterol as a means of reducing the risk for cardiovascular disease. Their primary action is to inhibit HMG-CoA reductase, an enzyme required for cholesterol biosynthesis. Stains bind to the active site of the enzyme, sterically preventing the substrate from binding. A significant percentage of the cholesterol in the body is synthesized by liver hepatocytes and this is the site of action of statins. The structures of 2 statins (pravastatin and simvastatin) are shown below. Pravastatin is administered in its active hydroxy acid form, while simvastatin is a prodrug that is enzymatically hydrolyzed in vivo to the active hydroxy form. Additional properties of these statins are in the table below: Но, co: Но, OH H2C нс" H.C HC „CH, CH HO Нас Simvastatin Pravastatin Molecular Weight pka LogP Bioavailability Plasma Protein Binding Hepatic Extraction Ratio Simvastatin 419 Nonelectrolyte 4.68 4% > 95% 0.95 Pravastatin 447 4.7 1.87 14% 50% 0.60 1. Even though the systemic bioavailability of statin drugs is low and hepatic extraction is high, they are still effective. Explain. 2. Simvastatin is a prodrug of its corresponding active hydroxy acid (simvastatin acid). Suggest a reason for developing a prodrug of simvastatin acid.
3. The elimination behavior of absorbed pravastatin and simvastatin is summarized below. Simvastatin Pravastatin Hepatic extraction ratio (ER) Elimination as unchanged drug 0.95 -0% (urine) -0% (feces) 16% (urine) 84% feces) 0.6 25% (urine) 75% (feces) -0% (urine) -0% (feces) Elimination as metabolites a. Hepatic extraction of drugs can be due to both hepatic metabolism and biliary secretion. Which process(es) are important for simvastatin? For pravastatin? Explain your reasoning. b. Based on their physicochemical properties, explain why pravastatin is eliminated unchanged in the urine to some extent, but simvastatin is not. 4. Simvastatin and simvastatin acid both undergo extensive metabolism by CYP3A4, converting them to inactive metabolites. Simvastatin acid is also metabolized by CYP2C8. a. Ritonavir (an HIV drug) and itraconazole (an antifungal drug) are strong CYP3A4 inhibitors. What does "inhibitor" mean? How will concomitant use of these drugs affect the metabolism and elimination of pravastatin and simvastatin?
b. A major toxicity of most statins is myopathy (severe muscle weakness), seen when there is higher than expected concentration of a statin in the body. A patient with HIV has been taking ritonavir chronically. His recent blood test showed a high cholesterol level, so his physician wants to put him on a statin. Which of the two statins would you recommend to minimize myopathy and why?