Simvastatin, a competitive inhibitor of HMG-CoA reductase, lowers cholesterol saturation index of gallbladder bile
✍ Scribed by William C. Duane; Donald B. Hunninghake; Martin L. Freeman; Pete A. Pooler; Linda A. Schlasner; Roger L. Gebhard
- Publisher
- John Wiley and Sons
- Year
- 1988
- Tongue
- English
- Weight
- 495 KB
- Volume
- 8
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
We tested the possibility that simvastatin, a competitive inhibitor of HMG-CoA reductase related to mevinolin, might alter cholesterol saturation of gallbladder bile. Ten patients with Type IIa or IIb hypercholesterolemia underwent bile sampling before, and again after, treatment with 20 or 40 mg per day simvastatin for 7 to 13 weeks. Mean cholesterol saturation index of gallbladder bile fell from 1.01 to 0.77 during simvastatin treatment (p < 0.01). This finding strongly suggests that treatment with HMG-CoA reductase inhibitors will not predispose to development of cholesterol gallstones. Indeed, it raises the possibility that such inhibitors might have a future role to play in treatment of gallstones.
Cholesterol is held in solution in bile by bile saltlecithin micelles (1). Secretion of excess cholesterol, relative to bile salt and lecithin, causes supersaturation of the bile and predisposes to formation of gallstones (1,2). This process can be reversed by ingestion of chenodeoxycholic acid or ursodeoxycholic acid. Both of these bile acids reduce hepatic cholesterol secretion, desaturate bile and promote dissolution of cholesterol gallstones (3-6). Certain hypocholesterolemic drugs, namely clofibrate and gemfibrozil, have exactly opposite effects. Both drugs increase biliary cholesterol secretion and increase saturation index of gallbladder bile (7, 8). Moreover, clofibrate is known to increase the incidence of clinical cholelithiasis (9).
Recently, a new class of hypocholesterolemic drugs has been developed. These drugs lower serum cholesterol by competitively inhibiting HMG-CoA reductase, the ratelimiting enzyme in cholesterol synthesis (11)(12). Whereas this mechanism of action is different from that of clofibrate and gemfibrozil, it nevertheless is possible that these reductase inhibitors might worsen biliary cholesterol saturation. Indeed, there is one report that acute administration of one such inhibitor to rats increased biliary cholesterol saturation (12).
On the other hand, chenodeoxycholic acid also lowers activity of HMG-CoA reductase (13-15), and this may