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Abstract

It has been recently shown that the newest hypocholesterolemic agent, simvastatin, lowers the biliary cholesterol saturation index and that its association with ursodeoxycholic acid renders it more effective. To determine the mechanism by which simvastatin decreases the biliary cholesterol saturation index, we evaluated hepatic secretion rates of cholesterol, bile acids and phospholipids, and cholic acid pool size, turnover and synthesis in eight hyperlipidemic patients (five women and three men, age range = 38 to 65 yr). These assessments were conducted before treatment, after 4 wk of simvastatin (40 mg/day), after 4 wk of ursodeoxycholic acid (600 mg/day) and after a further 4 wk of a combination therapy of simvastatin (40 mg/day) plus ursodeoxycholic acid (600 mg/day).

The cholesterol saturation index was significantly reduced with simvastatin (from 1.51 ± 0.10 to 0.94 ± 0.05, mean ± S.E.; p<0.02), with ursodeoxycholic acid (from 1.51 ± 0.10 to 0.86 ± 0.03, mean ± S.E.; p<0.02) and with the combination of simvastatin plus ursodeoxycholic acid (from 1.51 ± 0.01 to 0.70 ± 0.05, p<0.02). The cholesterol saturation index during combination therapy was significantly lower (p<0.02) than that reached during the use of simvastatin and ursodeoxycholic acid. Both simvastatin and ursodeoxycholic acid significantly reduced the hepatic secretion rate of cholesterol (from 130 ± 14 μmol/hr to 81 ± 12 μmol/hr, p<0.01, and 70 ± 9 μmol/hr, p<0.01) without affecting bile acid and phospholipid outputs. The combination induced a significantly greater decrease of biliary cholesterol output (from 130 ± 14 to 53 ± 5 μmol/hr). Cholic acid pool size, synthesis and turnover rate were not affected by simvastatin administration, but ursodeoxycholic acid and the combination therapy significantly increased (p<0.02) the turnover of cholic acid. Our study shows that simvastatin decreases the cholesterol saturation index by reducing the biliary cholesterol secretion rate and that a synergistic effect is obtained by the addition of ursodeoxycholic acid. (HEPATOLOGY 1992;15:1072–1078).