Effect of Pravastatin sodium, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on very-low-density lipoprotein composition and kinetics in hyperlipidemia associated with experimental nephrosis

Hirano, Tsutomu; Komuro, Fumiko; Furukawa, Seiichi; Nagano, Seishi; Takahashi, Takehiro

doi:10.1016/0026-0495(90)90026-9

Cited by 32 publications

(14 citation statements)

References 29 publications

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“…As compared with pravastatin, the lowering effect of fluvastatin on plasma TG was found to be more powerful and the hypertriglyceridemia in ne phrotic rats was completely normalized by the treatment. The daily consumption of fluvastatin in the present study was one fourth of that of pravastatin in previous experi ments [11,21], therefore, it is obvious that the hypolipidemic effect is greater in fluvastatin than in pravastatin.…”

Section: Discussionmentioning

confidence: 66%

“…We have previously reported that pravastatin, another water-soluble HMG CoA R inhibitor, slightly reduced plasma TG con centration in normal and nephrotic rats [11]. Yoshino et al [21] also reported the mild hypotriglyceridemic effect of pravastatin in normal rats.…”

Section: Discussionmentioning

confidence: 97%

“…Similarly, we [11] and others [21] reported a lack of hypocholesterolemic effects in rats treated with pravastatin. The reason for not observing a hypocholesterolemic effect remains unclear, but this may be attributable to species-specific differences in rats versus humans.…”

Section: Discussionmentioning

confidence: 99%

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Fluvastatin, a New Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, Suppresses very Low-Density Lipoprotein Secretion in Puromycin Aminonucleoside-Nephrotic Rats

Moritomo

Hirano²,

Ebara³

et al. 1994

Nephron

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The effects of fluvastatin, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the hyperhpidemia associated with nephrosis were studied. Nephrotic rats, induced by a single intraperitoneal injection of puromycin aminonucleoside (100 mg/kg body weight), had significantly higher plasma triglyceride (TG), total cholesterol and apoprotein (apo) B concentrations than controls. Fluvastatin was administrated as a 0.01% solution in drinking water for 14 days to either normal control or nephrotic rats. Concentrations of TG and apo B in plasma, and very low-density lipoprotein (VLDL) in nephrosis were completely normalized by the treatment with fluvastatin, but concentrations of cholesterol in plasma and each lipoprotein fraction were not altered by the treatment. The ratio of apo E to C in VLDL was significantly decreased in nephrotic rats, but the fluvastatin treatment increased this ratio. TG secretion rate estimated by the Triton WR1339 method was significantly increased in nephrotic rats, but was normalized by fluvastatin. Percent composition of TG in newly secreted VLDL particles in post-Triton plasma was not decreased by fluvastatin treatment, suggesting that the number of newly secreted VLDL particles was reduced by the treatment. Postheparin plasma lipolytic activities were not affected by the fluvastatin treatment. These results demonstrate that fluvastatin can effectively ameliorate the high concentration of VLDL by suppressing the hepatic secretion in nephrotic rats, and suggest that an inhibition of cholesterol biosynthesis suppresses VLDL secretion from the liver.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 97%

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Fluvastatin, a New Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, Suppresses very Low-Density Lipoprotein Secretion in Puromycin Aminonucleoside-Nephrotic Rats

Moritomo

Hirano²,

Ebara³

et al. 1994

Nephron

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“…Similar reductions in plasma triglycerides found in. Wistar rats after 14 days of treatment with 0,4% Pravastatin in the drinking water (Yoshino et al , 1988;Hirano et al, 1990), and after 7 days of treatment with O' 1% Mevastatin in the diet (Endo et al, 1979). The latter is 10 times the dietary concentration of Simvastatin used in the present study.…”

Section: Discussionmentioning

confidence: 99%

Subcutaneous administration of HMG-CoA reductase inhibitors in hyperlipidaemic and normal rats

Joles

Willekes-Koolschijn²,

Koomans³

et al. 1992

Lab Anim

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SummaryRecent reports demonstrate a hypocholesterolaemic effect of daily subcutaneous injections of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors in different rat models of hyperlipidaemia. However, this effect is not seen after oral administration of HMG-CoA reductase inhibitors in rats. We found that oral administration of the HMG-CoA reductase inhibitor Simvastatin also had no effect on plasma cholesterol in severely hyperlipidaemic Nagase analbuminaemic rats (NAR). Simvastatin (an apolar compound dissolved in propylene glycol) was infused continuously for 28 days into the subcutis of control Sprague-Dawley rats (SDR) and NAR using an implanted osmotic pump. All doses which were effective in reducing cholesterol in the NAR (reductions up to -60070), reduced apolipoprotein AI but not apolipoprotein B and caused a severe inflammatory reaction in the dermis. Similar toxicity was observed in the SDR. Subcutaneous administration of the vehicle (propylene glycol) did not cause this reaction and did not affect plasma lipids. Administration of Lovastatin in osmotic pumps resulted in a similar inflammatory reaction. Incorporation of Simvastatin into liposomes did not diminish the toxic effect.Correspondence to: Dr JA Joles, Department of Nephrology (F03.226), Utrecht University Hospital, PO Box 85500, 3508 GA Utrecht, The Netherlands. Received 14 October 1991; accepted 30 December 1991On the other hand, infusion of Pravastatin (a polar HMG-CoA reductase inhibitor dissolved in isotonic saline) caused no changes in the dermis and had no effect on plasma lipids in NAR or SDR. Liver microsomes prepared from the Pravastatin-treated rats demonstrated a 3-to 4-fold increase in HMG-CoA reductase activity as compared to untreated rats, confirming uptake of the drug. We conclude that continuous subcutaneous administration of the HMG-CoA reductase inhibitors Simvastatin, Lovastatin and Pravastatin for 28 days may not reduce plasma cholesterol in rats by a mechanism which is related to inhibition of HMG-CoA reductase activity in the liver. The decrease of plasma cholesterol effected by subcutaneous infusion of Simvastatin or Lovastatin in NAR coincides with, and may be related to inflammatory changes caused by administering these compounds into the dermis.

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“…A summary of the clopidogrel solubility data shown in Table 1 reveals that it is fairly soluble and stable in aqueous solution at low pH; however, the solubility drops steeply when the solution pH is above 3. Pravastatin sodium ( Figure 1B) is an HMG CoA reductase inhibitor, a class of lipid-lowering compounds that reduce cholesterol biosynthesis (7). Pravastatin sodium is the most soluble and stable at neutral pH and higher but degrades via lactonization and oxidation at about pH 4 and lower.…”

Section: Introductionmentioning

confidence: 99%

Development of a Single In Vitro Dissolution Method for a Combination Trilayer Tablet Formulation of Clopidogrel and Pravastatin

Huang¹,

Lozano²,

Francis³

et al. 2011

Dissolution Technol.

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A fixed-combination dose, trilayer tablet formulation was developed for two drugs already marketed as individual products, Plavix in which clopidogrel, an anti-clotting agent, is the active ingredient and pravastatin, an HMG-CoA reductase inhibitor for the treatment of hypercholesterolemia. To simplify quality control testing, the preference is to use a single dissolution method for the analysis of multiple active components in a combination tablet. However, development of one dissolution method for clopidogrel and pravastatin is particularly challenging because of the divergent pH solubility and pH dependent stability of these two drugs. At low pH (<3), clopidogrel bisulfate is most soluble and stable, whereas pravastatin sodium rapidly degrades due to lactonization and oxidation. Conversely, at a neutral pH and higher, pravastatin sodium is most soluble and stable, but clopidogrel bisulfate undergoes hydrolysis and racemization. This article describes the development of a single dissolution method to accommodate both drugs, including selection of medium pH and surfactant. The method uses USP Apparatus 2 (paddles) at 75 rpm in 1000 mL of citrate buffer (0.05 M, pH 5.5) medium containing 2% CTAB (cetyltrimethyl ammonium bromide, a cationic surfactant) at 37 °C. This dissolution methodology provides good dissolution profiles for both clopidogrel and pravastatin and is able to discriminate the changes in composition, manufacturing process, and stability for the combination tablets. To quantitate both drugs simultaneously, a rapid isocratic reversed-phase liquid chromatographic method was developed and validated.

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Effect of Pravastatin sodium, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on very-low-density lipoprotein composition and kinetics in hyperlipidemia associated with experimental nephrosis

Cited by 32 publications

References 29 publications

Fluvastatin, a New Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, Suppresses very Low-Density Lipoprotein Secretion in Puromycin Aminonucleoside-Nephrotic Rats

Fluvastatin, a New Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, Suppresses very Low-Density Lipoprotein Secretion in Puromycin Aminonucleoside-Nephrotic Rats

Subcutaneous administration of HMG-CoA reductase inhibitors in hyperlipidaemic and normal rats

Development of a Single In Vitro Dissolution Method for a Combination Trilayer Tablet Formulation of Clopidogrel and Pravastatin

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