Effect of simvastatin (MK-733) on plasma triacylglycerol levels in rats

The effect of simvastatin (MK-733), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on plasma triacylglycerol (TG) levels was studied in rats. Dietary administration of MK-733 (0.055%, w/w) for 7 days significantly (P less than 0.05) reduced plasma TG levels by 30.6% associated with a 44.3% significant (P less than 0.01) reduction in very low density lipoprotein TG (VLDL-TG) as compared to those in the concurrent control rats. Clofibrate (0.08%, w/w) also significantly (P less than 0.05) decreased plasma TG levels by 26.1%. MK-733 did not affect the triacylglycerol secretion rate (TGSR) during 0-1.5 hr after administration of Triton WR-1339, but reduced it by 33.9% during 1.5-3.0 hr. Clofibrate also decreased TGSR during 1.5-3.0 hr. MK-733 increased lipoprotein lipase (LPL) activity in epididymal adipose tissue and thigh muscle by 36.3 and 55.0% respectively. MK-733 significantly (P less than 0.05) increased LPL activity in the post-heparin plasma by 21.5%, although it did not affect hepatic triacylglycerol lipase (H-TGL) activity. Clofibrate did not affect LPL activity in the tissues or LPL and H-TGL activities in the post-heparin plasma. It is considered that the mechanism of plasma TG-lowering effect of MK-733 is the removal of VLDL-TG by an increase in LPL activity in the tissues as well as a decrease in the TGSR.     

Effects of simvastatin (MK-733) on branched pathway of mevalonate

The effects of simvastatin (MK-733), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on the branched pathway of mevalonate metabolism were studied in Hep G2 cells. The synthesis of cholesterol, ubiquinone and dolichol were examined using various radiolabeled precursors. The effect on DNA synthesis was also determined. MK-733 at a concentration of 1 microM potently inhibited the incorporation of [3H]acetate into cholesterol (84%) without affecting that from [3H]mevalonolactone. Under these conditions, MK-733 reduced the incorporation of L-[14C]tyrosine into ubiquinone slightly (14%), although it did not suppress that from [3H] acetate. The incorporation of [3H]acetate into dolichol was slightly reduced by MK-733. On the contrary, the incorporation of [3H]mevalonolactone into ubiquinone and dolichol was increased by MK-733. This apparent increase in incorporation was thought to be largely due to the higher specific radioactivity of the intracellular pool of mevalonate. The present study demonstrated that MK-733 slightly suppressed the synthesis of ubiquinone and dolichol in Hep G2 cells. However, the extent of their reduction was far less than the effect on cholesterol synthesis, suggesting that there were differences in substrate affinity between the enzymes participating in the cholesterol synthetic pathway and those in the ubiquinone or dolichol synthetic pathway. Furthermore, MK-733 did not affect DNA synthesis even at a concentration of 10 microM.     

Effect of pitavastatin on sterol and bile acid excretion in guinea pigs

The influence of pitavastatin (CAS 147526-32-7), a potent 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, exerted on fecal and biliary excretion of sterols and bile acids was investigated using guinea pigs. The cumulative amount of [3H] bile acid in bile 0 to 6 h after the injection of high density lipoprotein (HDL), which was labeled with [3H] cholesteryl ester (CE), was slightly decreased with atorvastatin (30 mg/kg, CAS 134523-00-5) and simvastatin (30 mg/kg, CAS 79902-63-9), and the same level as the control was maintained with pitavastatin (3 mg/kg). The amount of excretion of [3H] sterol into bile was significantly increased with atorvastatin and simvastatin, and exhibited a tendency to decline with pitavastatin. The [3H] bile acid/[3H] sterol ratios were significantly lowered with atorvastatin and simvastatin by 41% and 29%, respectively, as compared to the control, and exhibited an upward tendency with pitavastatin (22%). The total amounts of fecal [3H] bile acid from 0 to 7 days were significantly decreased with atorvastatin and simvastatin by 30% and 32%, respectively, and slightly increased with pitavastatin by 8% Furthermore, mRNA expression of the hepatic microsomal cytochrome P-450 enzyme, cholesterol-NADPH: oxygen oxidoreductase (cholesterol 7 alpha-hydroxylase; CYP7A), which is a late limiting enzyme with a bile acid composition, was also decreased with atorvastatin and simvastatin by 54% and 38%, respectively, and slightly increased with pitavastatin (14%). The change in CYP7A mRNA expression was well correlated with the amount of the fecal [3H] bile acid. The bile acid excreting efficacy of pitavastatin was relatively high as compared with atorvastatin or simvastatin. It is suggested that this action may contribute to the powerful cholesterol lowering action of pitavastatin.     

Effect of simvastatin (MK-733) on the regulation of cholesterol synthesis in Hep G2 cells

A new antihypercholesterolemic drug, simvastatin (MK-733), which is a prodrug of a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, inhibited cholesterol synthesis from [14C]acetate concentration dependently without inhibiting it from [3H]mevalonate in Hep G2 cells. Therefore, MK-733 is thought to be converted to L-654,969, the active beta-hydroxy acid form of MK-733 in the cells and/or medium. MK-733 inhibited cholesterol ester synthesis, but did not affect phospholipid, free fatty acid and triacylglycerol synthesis. This compound increased HMG-CoA reductase activity concentration dependently and raised the specific binding, internalization and degradation of 125I-labeled low density lipoprotein by Hep G2 cells. Another HMG-CoA reductase inhibitor, pravastatin (CS-514), also behaved like MK-733. However, its potency was far less than that of MK-733.     

Preventive effect of MK-733 (simvastatin), an inhibitor of HMG-CoA reductase, on hypercholesterolemia and atherosclerosis induced by cholesterol feeding in rabbits

MK-733 was found to prevent an increase of serum cholesterol levels in cholesterol-fed rabbits, and lovastatin also markedly inhibited their increase. MK-733 and lovastatin inhibited the increase of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) cholesterol, and it slightly affected the high density lipoprotein (HDL) cholesterol levels. MK-733 and lovastatin suppressed the increase of serum phospholipid levels and slightly affected the triglyceride levels. MK-733 suppressed the development of atherosclerosis in coronary arteries and aorta, and lovastatin also diminished their development.     

辛伐他汀对高脂饲喂家兔血脂的影响

目的：验证ＨＭＧ－ＣｏＡ还原酶抑制剂辛伐他汀的降血脂作用。方法：用含３％胆固醇饲料饲喂家兔、造成高脂血症模型。考察灌胃给药对血脂的影响。结果：口服辛伐他汀可剂量依赖性地抑制血清总胆固醇（ＴＣ）、甘油三酯（ＴＧ）的升高,对ＴＣ作用显著,ＴＧ有较微降低,对高密度脂蛋白（ＨＤＬ－Ｃ）有升高趋势,肝脏ＴＣ亦显著降低。降血脂作用与等剂量阳性对照药舒降之比较差异不显著。结论：国产辛伐他汀对血脂升高具有预防作用     

Influence of drugs on bile acid excretion.

The hydroxylation of bile acids in rat liver microsomes in cyt P-450 dependent (Bj?rkhem et al., 1975). To find out possible interactions between drugs and bile acid hydroxylation and/or active transport mechanisms we investigated the influence of the microsomal inhibitor metyrapon, the microsomal inducer phenobarbital and the intrahepatic cholestasis producing agents chlorpromazine, phenylbutazone and progesteron on bile flow and bile acid excretion. The excretion in monohydroxy (MBA), dihydroxy (DBA) and trihydroxy (TBA) bile acids were estimated in bile-fistula rats in three one hour periods. MBA, DBA and TBA were separated with thinlayer-chromatography and estimated fluorimetrically. Bile flow, bile acid excretion and relation TBA/DBA were influenced by acute and subchronic administration of the above mentioned drugs in different ways.     

Effect of phenobarbital on bile flow and bile salt excretion in the rat

Summary Treatment of rats with phenobarbital for 3 or 7 days increases bile flow to 150% or 151% of controls. This choleresis is not due to an increase of total bile acid output nor to a change of the bile acid pattern in bile.A preliminary report was presented at the 5th Meeting of the European Association for the Study of the Liver, Berne, September 1970.The advice of Dr. V. Scheiber (Computer-Station der Medizinischen Fakultät Wien) and the technical assistance of Mr. P. Sichrovsky are gratefully acknowledged.     

Fundamental studies on excretion of pivmecillinam in bile (author's transl)

Excretion of pivmecillinam (PMPC) in bile was investigated using normal and hepatic disorder (intramuscular injection of carbon tetrachloride, 0.5 g/kg twice) rabbits. Bile and blood were collected hourly (0.5 approximately 8 hours) and both concentrations and rates between both (passage), and excretion rates were investigated. Ampicillin (AMPC) was chosen as a control drug. 1. When PMPC was given orally to the normal rabbit in a dose of 200 mg/kg, a bile concentration after 0.5 hour was 138.08 microgram/ml and a peak value was attained. The rate to plasma concentration was 22.67. An excretion rate was 0.224%. When PMPC was given orally to the hepatic disorder rabbit in a dose of 200 mg/kg, a bile concentration after 0.5 hour was 26.67 microgram/ml. A peak value of 28.87 microgram/ml was attained after 4 hours. Their rates to plasma concentrations were 13.27 and 8.02, respectively. An excretion rate was 0.058%. Bile and plasma concentrations, rates of bile to plasma and excretion rates of the hepatic disorder group were lower than those of the normal group. Disturbances of hepatic functions were checked by biochemical tests, i.e. GOT, and so on. 3. When ABPC as a control drug was given orally to the rabbit in a dose of 200 mg/kg, plasma concentrations of hepatic disorder group were higher than those of the normal group, but rates of bile to plasma concentrations and excretion rates of the hepatic disorder group were lower than those of the normal group. 4. Bile concentrations and excretion of PMPC were significantly higher than those of ABPC in the normal group. In the hepatic disorder group, however, no statistical difference was observed between them.     

Effect of ursodeoxycholic acid administration on bile acid composition in hamster bile

The modification in the composition of bile acids in hamster by the administration of high dose of ursodeoxycholic acid (UDCA) was investigated. Male Golden Syrian hamsters were divided into five groups: a control group, two groups that received 0.5 g of UDCA per 100 g of standard diet during 30 and 60 days and another two groups that received 1 g of UDCA per 100 g of standard diet during 30 and 60 days. After ether anaesthesia the gallbladder was removed and bile was immediately aspirated. Bile acids were determined by high performance liquid chromatography (HPLC). Taurolithocholic (TLCA) and glycolithocholic acids (GLCA) increased significantly in all treated groups. The glyco/tauro ratio of 0.69 in controls became more than 1 in treated animals except in the case of lithocholic acid (LCA) conjugates which remained less than 1. UDCA derivatives increased proportionally to the administered dose and the cholic/cheno ratio diminished significantly. A moderate increase of 3- and 7-keto derivatives of chenodeoxycholic acid (CDCA) was observed in all treated groups but the above mentioned increment was especially evident in 3-keto derivatives. A high percentage of UDCA administered in the hamster was likely transformed to CDCA and the glyco conjugates of the bile acids were the predominant species except for the LCA derivatives.     

Effect of iron poly (sorbitol-gluconic acid) complex on urinary cellular excretion

Summary

The intramuscular injection of 250?mg iron poly (sorbitol-gluconic acid) complex-caused no increase in urinary cellular or bacterial excretion in 8 patients with chronic-pyelonephritis, 4 patients with non-infective renal disease, and 4 controls. However, in 4 patients with chronic infective disease of the renal tract given 500?g there was a significant increase in cellular excretion. This response was not seen in 2 control patients, nor in 2 patients with non-infective renal disease. Using a differential staining technique, this increase in urinary cellular excretion was found to be due, not to leucocytes, but to renal tubular cells. The precise significance of this is unclear, but there would be concern that the high concentration of excreted iron was providing a ‘toxic’ insult to susceptible, infection-damaged cells.     

辛伐他汀抑制心肌细胞Rho A、Rho GTPase表达对心室肥厚的影响

目的 探讨辛伐他汀对心力衰竭模型兔抑制心肌肥厚、改善心功能的影响及机制.方法 24只新西兰白兔,均分四组.除假手术组外,通过破坏主动脉瓣和缩窄腹主动脉,增加左心室前、后负荷,建立慢性心力衰竭模型;术后(除心衰对照组)早干预组(即起,连续8周)和晚干预组(第5周起,连续4周)予辛伐他汀每天5 mg/kg灌胃,实验结束取心肌细胞,Westem-blot检测细胞膜Rho A蛋白表达,[γ~-~(32)P]电泳分析Rho GTPase活性;实验前、结束时均行超声心动图检查.结果 心衰对照组室间隔厚度(LVSd)、左心室舒张期内径(LVIDd)、左心室后壁厚度(LVPwd)、左心室收缩期内径(LVIDs)、心脏重量(Hw)、左心室重量(LVW)、心脏/体重(HW/BW radio)、左心室/体重(LVW/BW radio)明显高于假手术和早、晚干预组(P<0.05,P<0.01);左室射血分数(EF)、左室长轴缩短率(FS)明显低于假手术组和早、晚干预组(P<0.05,P<0.01);心肌细胞膜Rho A蛋白表达、Rho GTPase活性明显高于假手术组和早、晚干预组(P<0.01).结论 辛伐他汀可抑制细胞膜RhoA蛋白表达、Rho GTPase活性,从而抑制心肌肥厚、改善心功能.     

Effect of probenecid on the excretion of ampicillin in human bile

1. Ampicillin concentrations were determined in serum and bile after intravenous injection into patients with T-tube bile drainage of 1 gram ampicillin before and during probenecid medication. The concentrations were followed up to fifteen hours after injection.2. Probenecid increased the half-life of ampicillin in serum from 74 minutes to 137 minutes.3. Ampicillin concentrations in bile were higher following probenecid medication and a concentration over 5 mug/ml was obtained for 3 h longer than before probenecid.4. The ampicillin concentrations in bile were approximately the same as those in serum both before and during probenecid medication suggesting passive transport of ampicillin from blood to bile.5. A combined treatment of ampicillin and probenecid might be of clinical value in the therapy of cholangitis and typhoid carriers.     

Effect of short-term bile duct ligation on peripheral blood steroids urinary PGE2 and the rate of sodium excretion in male rabbits

• 1.1. Short-term bile duct ligation in male rabbits resulted in a significant reduction in the rate of sodium excretion after saline challenge (10 ml/kg/hr for 4 hr, P < 0.03).
• 2.2. The reduction in the sodium excretory rate (14.3 ± 7.8 to 6.3 ± 5 μ-equiv/min, P < 0.03) was associated with an increased urinary PGE₂ excretion (200.9 ± 174 to 731.8 ± 1039.8 pg/min, P < 0.01) without significant change in serum aldosterone and cortisol concentrations.
• 3.3. Serum progesterone concentration increased (37.2 ± 15.6 to 119.2 ± 34.6 ng/dl, P < 0.01) whereas serum 17-hydroxyprogesterone concentration declined after bile duct ligation suggesting the development of a 17-hydroxylase enzymatic block.