Effects of long-term treatment with low-dose pravastatin on biliary lipid and bile acid composition in patients with nonfamilial hyperlipoproteinemia

Tazuma, Susumu; Takizawa, Itsuo; Kunita, Tetsuro; Mizuno, Toshiyuki; Watanabe, T.; Teramen, Kazushi; Horikawa, Kazuhiko; Ochi, Hidenori; Yamashita, Yoshifumi; Aihara, Naoki; Sasaki, Makoto; Hirano, Naomichi; Miura, Hiroyuki; Hatsushika, Sumie; Ohya, Toshihide; Kajiyama, Goro; Itoh, Katsuhide

doi:10.1016/0026-0495(95)90138-8

Cited by 13 publications

(19 citation statements)

References 18 publications

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“…Secretion of biliary cholesterol, bile acids, and of phospholipids decreased by 46%, 36%, and 51% after pravastatin, respectively. As a consequence, cholesterol saturation of bile remained essentially unchanged as described previously, [57][58][59] although some investigators found a decrease during pravastatin. 23,60 Notably, pravastatin and cerivastatin 61 administration may differ from lovastatin and simvastatin because of less effective lowering of biliary cholesterol saturation compared with bile acid and phospholipid secretion.…”

Section: Discussionsupporting

confidence: 77%

The pravastatin-induced decrease of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis in humans

et al. 1999

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3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to suppress biliary cholesterol secretion and saturation. It remains unproven whether this is mediated by inhibition of cholesterol synthesis. Therefore, the effect of a long-term administration of pravastatin on cholesterogenesis and on biliary lipid secretion was investigated in seven healthy volunteers. Placebo or 40 mg of pravastatin were taken daily at bedtime for 5 weeks using a double-blind crossover design. During the last week, 12 hours after the last drug intake 0.04 mmol [1-13 C]acetate/kg · h and 0.5 g polyethylene glycol 4,000/h were infused intraduodenally for 15 hours. Plasma and duodenal bile samples were collected hourly. Thereafter, the decay of [ 13 C]labeled plasma cholesterol was measured during the following 3 days. The fractional and absolute syntheses of plasma and biliary cholesterol were determined by gas chromatography mass spectrometry using mass isotopomer distribution analysis. At the end of the pravastatin period plasma total and low-density lipoprotein (LDL) cholesterol had decreased by 20% and 24%, respectively. Similarly, pravastatin suppressed biliary secretion rates of cholesterol, total bile acids and phospholipids (P F .05) by 46%, 36%, and 51%. As a consequence, cholesterol saturation index remained unchanged. However, fractional syntheses of cholesterol were comparable (P G .05) on placebo compared with pravastatin with 3.1% versus 4.0% in plasma and 4.3% versus 5.2% in bile after 15 hours, respectively. The mean absolute synthesis rates amounted to 0.3 mg/kg/h on placebo versus 0.4 on pravastatin (P G .05). In conclusion, the pravastatin-induced reduction of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis. (HEPATOLOGY 1999;30:14-20.)A variety of defects are realized to explain the pathogenesis of cholesterol gallstone formation, including cholesterol supersaturation as well as gallbladder hypomotility, rapid nucleation, and a mucin hypersecretion. Most likely a sustained cholesterol supersaturation of bile 1 owing to hepatic hypersecretion of cholesterol 2 stands at the beginning of this process. In animal studies the origin of biliary secreted cholesterol has been well defined. In rats and hamsters the amount of newly synthesized cholesterol secreted into bile amounts to 8% to 18% and 2% to 5%, respectively. [3][4][5][6] In humans, most of the indirect evidence using standard radioisotope kinetics supported that 20% of biliary cholesterol were derived from de novo synthesis, 7 the majority being preformed cholesterol supplied by high-density lipoprotein cholesterol. 8 We have recently shown that the mass isotopomer distribution analysis (MIDA) technique allows for the direct measurement of the 4% to 5% of newly synthesized cholesterol formed from [ 13 C]acetate in bile and also that a significantly higher proportion of de novo cholesterol is secreted into bile as opposed to plasma in healthy individuals' circulation. 9 Thus, it seems tha...

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Section: Discussionsupporting

confidence: 77%

The pravastatin-induced decrease of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis in humans

et al. 1999

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“…Lipid-lowering drugs can have a significant effect on biliary lipid composition (6-8). Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzymatic step in cholesterol biosynthesis, commonly referred to as statins, have revolutionized the treatment of hypercholesterolemia and have been recently shown to exert beneficial effects beyond reducing serum cholesterol levels (9-12).…”

Section: Introductionmentioning

confidence: 99%

“…These observations suggest that statins may reduce bile lithogenicity. However, studies of the effects of statins on gallstone disease in humans have been conflicting (7, 8, 23-25). The results of these clinical or experimental studies have been limited by small sample size or lack of long-term follow-up.…”

Section: Introductionmentioning

confidence: 99%

Statin Use and the Risk of Cholecystectomy in Women

et al. 2009

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“…Furthermore, the cholesterol saturation index (SI) of gall bladder bile has been reported to be reduced by some3-6 but not all7-11 authors during short term administration of simvastatin, pravastatin, or lovastatin. Differences in patient selection, length of treatment,13 or pretreatment cholesterol SI9 12 may explain these discrepancies, and the effect of statins on biliary lipids is still not certain.…”

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confidence: 99%

Effect of long term simvastatin administration as an adjunct to ursodeoxycholic acid: evidence for a synergistic effect on biliary bile acid composition but not on serum lipids in humans

Lotti

Panarotto

Sorbara

et al. 1999

Gut

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Background-Stimulated bile acid synthesis preferentially utilises newly synthesised cholesterol, raising the posssiblity that combination of simvastatin (an inhibitor of cholesterol synthesis) with ursodeoxycholic acid (UDCA; a stimulator of bile acid synthesis) may result in reduced bile acid synthesis and greater enrichment of the pool with UDCA than that achieved with UDCA treatment alone. Aims-To investigate the eVect of simvastatin and UDCA given alone and in combination on serum and biliary lipid and biliary bile acid composition. Methods-Eighteen patients with primary non-familial hypercholesterolaemia were studied during treatment with simvastatin 20 mg/day, UDCA 10 mg/kg/day, and a combination of the two drugs. Each regimen was given in random order for three months following a three month lead in period. Results-Simvastatin significantly reduced serum low density lipoprotein (LDL) cholesterol but biliary cholesterol concentration remained unchanged. Combination of the two drugs had no synergistic eVect on serum cholesterol concentration, but significantly increased the proportion of UDCA in the bile acid pool from 35% during UDCA to 48% during combination treatment (p<0.04). Conclusions-Results showed that: (1) simvastatin reduces serum LDL cholesterol but has no eVect on biliary cholesterol concentration, supporting the concept that newly synthesised cholesterol is not the preferential source for biliary cholesterol; and (2) combination of simvastatin with UDCA has the predicted eVect of enhancing the proportion of UDCA in the pool. This eVect may be of benefit in the treatment of cholestatic liver diseases. (Gut 1999;44:552-556)

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Effects of long-term treatment with low-dose pravastatin on biliary lipid and bile acid composition in patients with nonfamilial hyperlipoproteinemia

Cited by 13 publications

References 18 publications

The pravastatin-induced decrease of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis in humans

The pravastatin-induced decrease of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis in humans

Statin Use and the Risk of Cholecystectomy in Women

Effect of long term simvastatin administration as an adjunct to ursodeoxycholic acid: evidence for a synergistic effect on biliary bile acid composition but not on serum lipids in humans

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