Statin drugs

Once has been determined in the absence of inhibitor, can be calculated from equation (47). K, values are used to compare different inhibitors of the same enzyme. The lower the value for K, the more effective the inhibitor. For example, the statin drugs that act as competitive inhibitors of HMG-CoA reductase (Chapter 26) have values several orders of magnimde lower than the AT for the substrate HMG-CoA. 

Scheme 11. Aldolase-catalyzed synthesis of statin drugs via the megagenonuc approach...

Inhibit Enzymes Many drugs are competitive inhibitors of key enzymes in pathways. The statin drugs (lovastatin, simvastatin), used to control blood cholesterol levels, competitively inhibit 3-hvdroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in cholesterol biosynthesis. Methotrexate, an antineoplastic drug, competitively inhibits dihydrofolate reductase, depriving the cell of active folate needed for purine and deoxythymidine synthesis, thus interfering with DNA replication during S phase. 

Hydroxy-3-methylglutaryl (HMG)-CoA reductase on the smooth endoplasmic reticulum (SER) is the rate-limiting enzyme. Insulin acth"ates the enzyme (dephosphorylation), and glucagon inhibits it. Mevalonate is the product, and the statin drugs competitively inhibit the enzyme. Cholesterol represses the expression o the HMG-CoA reductase gene and also increases degradation of the enzyme. 

G Patients requiring cholesterol-lowering drugs Prescription drug One or more statin drugs Manufactured capsule Ingestion... 

The results of several large clinical trials using the statin drugs (discussed later) show that the tested drugs decreased the risk of both primary and secondary cardiovascular events. The incidence of myocardial infarction and death from cardiovascular disease was reduced in patients with hypercholesterolemia who never had a... 

An article in the New England Journal of Medicine reports that 24 patients taking fen-phen, a combination of two weight-reduction drugs, have an unusual form of heart disease involving abnormalities in the heart valves. The FDA approves Baycol, an anticholesterol statin drug made by Bayer. It costs less than competitors but turns out to have a rare but serious side effect that destroys muscle tissue. 

Pfizer merges with Warner-Lambert and gains the rights to the highly successful anticholesterol statin drug Lipitor. 

August 8 Bayer withdraws its statin drug Baycol from the market after analysis of new data shows that 31 patients taking the drug had died from rhabdomyolysis, a rare disease that destroys muscle tissue. 

The world s largest pharmaceutical company makes the anticholesterol statin drug Lipitor, the antidepressant Zoloft, and the erectile... 

Cyclosporine prolongs the half-life of statin drugs. Therefore, in transplant recipients, the preferred dose of these cholesterol-lowering agents is half of the recommended dose. Some of these agents have been reported to cause rhabdomyolysis when given to patients receiving cyclosporine-A. 

Inhibition by drugs The statin drugs, including simvastatin, lovastatin, and mevastatin, are structural analogs of HMG CoA, and are reversible, competitive inhibitors of HMG CoA reductase (Figure 18.7). They are used to decrease plasma cholesterol levels in patients with hypercholesterolemia.1... 

X.S. Miao, C.D. Metcalfe, Determination of cholesterol-lowering statin drugs in aqueous samples using liquid chromatography-electrospray ionization tandem mass spectrometry, J. Chromatogr. A 998 (2003) 133-141. 

Research on the pathway of cholesterol biosynthesis led to the development of a new class of drugs called statins. All statins, including atorvastatin (Lipitor, 2.22) and rosuvastatin (Crestor, 2.23), are inhibitors of the enzyme HMG-CoA reductase (Figure 2.6). Structurally, the acid side chain found on statin drugs closely resembles mevalonic acid (2.18). The side chain plays an important role in the binding of statins to HMG-CoA reductase. 

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