LC separation and induced fluorometric detection of rivastatin in blood plasma

Krol, G.J.; Beck, G; Ritter, W.; Lettieri, John

doi:10.1016/0731-7085(93)80113-f

Cited by 25 publications

(24 citation statements)

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“…The effects of cerivastatin were obtained at 50 nmol/L and above, within the range of concentrations obtained in humans with the highest clinically used dose (0.8 mg/d). 41 They are also in the range of concentrations found to be effective in previous studies in rabbits. 42,44 The dose-related effects of the other statins were obtained at 100-fold higher concentrations, consistent with their known potencies against HMG-CoA reductase and the higher clinical doses 10 to 80 mg/d.…”

Section: Discussionmentioning

confidence: 67%

“…Secretion of all 3 MMPs was decreased 52Ϯ19%, 71Ϯ18%, and 73Ϯ17%, respectively (PϽ0.01, nϭ3) by 50 nmol/L cerivastatin, a plasma concentration previously shown to be associated with cholesterol-lowering effects in vivo. 41,42 Lov-astatin at a concentration of 5 mol/L also inhibited IL-␣ and PDGFBB-stimulated MMP-1, -3, and -9 secretion by 94Ϯ5%, 78Ϯ24%, and 74Ϯ9.8%, respectively (PϽ0.01, nϭ3) ( Figure I, available online at http://atvb.ahajournals. org), consistent with the relative potencies of cerivastatin and lovastatin as HMGCoA reductase inhibitors.…”

Section: Statins Inhibit Mmp-1 -3 and -9 Production From Human Vsmcsmentioning

confidence: 99%

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Statins Inhibit Secretion of Metalloproteinases-1, -2, -3, and -9 From Vascular Smooth Muscle Cells and Macrophages

Luan

Chase

Newby

2003

ATVB

311

213

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Objective-Production of several metalloproteinases (MMPs) from smooth muscle cells (SMCs) and macrophages causes matrix destruction and atherosclerotic plaque instability. Statins, which inhibit HMG-CoA reductase and hence cholesterol and isoprenoid synthesis, stabilize plaques. We investigated whether statins inhibit MMP secretion from SMCs and macrophages. Methods and Results-We used human saphenous vein and rabbit aortic SMC and foamy macrophages from cholesterol-fed rabbits. Cerivastatin (50 nmol/L) inhibited inducible MMP-1, -3, and -9 secretion from human SMC by 52Ϯ19%, 71Ϯ18%, and 73Ϯ17%, respectively (PϽ0.01, nϭ3). Similar dose-related effects of cerivastatin (50 to 500 nmol/L), simvastatin (1 to 20 mol/L), and lovastatin (5 to 20 mol/L) were consistent with their relative potencies against HMG-CoA reductase. Statins also inhibited inducible MMP-1, -3, and -9 and constitutive MMP-2 secretion but not TIMP-1 or -2 secretion from rabbit SMC. Statins also dose-dependently inhibited MMP-1, -3, and -9 secretion from rabbit foam cells; cerivastatin (50 nmol/L) inhibited by 68Ϯ18%, 74Ϯ14%, and 74Ϯ14%, respectively (PϽ0.01, nϭ4 [3][4][5][6] Overexpression of MMPs, including MMP-1, MMP-3, and MMP-9, has been demonstrated in human and animal atherosclerotic plaques, [7][8][9][10][11][12][13][14][15][16] where it is colocalized with morphological and mechanical determinants of plaque rupture. MMPs together can catalyze the complete destruction of interstitial collagen, 17 which is the main component of fibrous caps responsible for their tensile strength. Loss of collagen leads to structural weakness and less resistance to the mechanical stresses imposed during systole. 18 This results ultimately in plaque rupture, the key event in triggering coronary thrombosis and hence acute coronary syndromes such as unstable angina and myocardial infarction. 19 Expression of MMPs-1, -3, and -9 is upregulated in cells present in atheromas, including endothelial cells, 20 VSMCs, 21-25 and macrophages. 26 -29 Inflammatory mediators, including interleukin-1 (IL-1), CD-40 ligand, and tumor necrosis factor-␣, upregulate MMP activity in vascular cells, especially in combination with platelet-derived growth factor (PDGF) or basic fibroblast growth factor. 23,25 Tissue inhibitors of metalloproteinases (TIMPs) are a family of naturally occurring specific inhibitors of MMPs whose activity in atherosclerotic plaques seems to correlate with decreased MMP activity 30,31 and hence reduced matrix remodelling.Statins are a structurally related group of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are widely used to treat hyperlipidemia. Their use is associated with significant reduction of adverse coronary events, including myocardial infarction, and a marginal regression of plaque size. 32,33 Furthermore, recent studies, both in vitro and in vivo, have suggested that the beneficial effects of statins may extend to mechanisms beyond cholesterol reduction. [33][34][35][36] These pleiotropic effects of statins are mediate...

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Section: Discussionmentioning

confidence: 67%

Section: Statins Inhibit Mmp-1 -3 and -9 Production From Human Vsmcsmentioning

confidence: 99%

Statins Inhibit Secretion of Metalloproteinases-1, -2, -3, and -9 From Vascular Smooth Muscle Cells and Macrophages

Luan

Chase

Newby

2003

ATVB

311

213

View full text Add to dashboard Cite

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“…Although it was reported that the plasma concentration of cerivastatin was increased by an oral administration in humans (Krol et al, 1993) and various animals (Steinke et al, 1996), an extremely low plasma drug concentration and no decrease in the plasma lipid levels were observed when cerivastatin was given to WHHL rabbits orally. Therefore, we administered cerivastatin to rabbits by subcutaneous injection in this study.…”

Section: Discussionmentioning

confidence: 99%

“…Blood samples were obtained from the marginal ear vein of each rabbit at 0.5, 1.0, 2.0, 4.0 and 6.0 h after drug injection. The plasma cerivastatin concentration was determined using HPLC equipped with a Lichrospher 100 RP-18 column according to the method of Krol et al (1993) with slight modi®cation. We analysed T max, C max, and the area under the concentration curve (AUC) from 0 ± 6 h.…”

Section: Plasma Concentration Of Cerivastatinmentioning

confidence: 99%

Effect of cerivastatin sodium, a new inhibitor of HMG‐CoA reductase, on plasma lipid levels, progression of atherosclerosis, and the lesional composition in the plaques of WHHL rabbits

Shiomi

Ito

1999

British J Pharmacology

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1 The aim of this study was to examine whether cerivastatin sodium, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a ects the lesional composition of spontaneously developed atherosclerosis due to hypercholesterolaemia and delays progression of the lesions. 2 We administered cerivastatin to 2-month-old WHHL rabbits, a low-density lipoprotein receptorde®cient animal model, at a dose of 0.6 mg kg 71 day 71 for 32 weeks. We examined the plasma lipid levels, the severity of atherosclerosis, and composition of atherosclerotic lesions. Lesional composition was determined using immunohistostaining for macrophages and smooth muscle cells, and Azan-Mallory staining for collagen ®bres and extracellular lipid deposits. 3 Compared to the control group, the plasma cholesterol levels were decreased in the treated group by 39% (12.7+0.6 mmol L 71 versus 20.9+1.0 mmol L 71 , P50.001). Atherosclerosis was suppressed by about 37% as measured by the thickness of the aortic lesions (158+13 mm versus 250+15 mm, P50.001), and by 28% as measured by coronary stenosis (62.7+11.4 versus 86.9+12.2, P50.05). In the cerivastatin group, regarding the per cent areas of lesional components in the lesion area, the macrophages (21.0+1.5% versus 27.9+1.9%, P50.01) and extracellular lipid deposits (3.2+0.4% versus 5.1+0.4%, P50.001) were decreased in the aortic lesions, and the per cent area of macrophages in the coronary lesions was also decreased (4.9+1.4% versus, 11.6+2.4%, P50.05). The per cent area of smooth muscle cells and collagen ®bres did not signi®cantly decrease. 4 These results indicate that cerivastatin contributed to the plaque stabilization and delayed progression of early atherosclerosis in young WHHL rabbits, in addition to the potent hypolipidemic e ects.

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“…Specific and sensitive high-performance liquid chromatographic (HPLC) assays employing post-column photochemical derivatization with ultraviolet light and subsequent fluorescence detection were used in all pivotal investigations to determine cerivastatin and/or metabolite plasma and urine concentrations (33). The assays were fully validated according to European guidelines.…”

Section: Assaysmentioning

confidence: 99%