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1. 7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1h-indol-2-yl)-3,5-dihydroxy-6-heptenoate
2. Fluindostatin
3. Fluvastatin
4. Fluvastatin Sodium
5. Fluvastatin Sodium Salt
6. Lescol
7. Xu 62 320
8. Xu 62-320
9. Xu 62320
10. Xu-62320
11. Xu62320
1. Fluvastatina
2. Fluvastatinum
3. 93957-54-1
4. 155229-76-8
5. Fluindostatin
6. Fluvastatine [inn-french]
7. Fluvastatinum [inn-latin]
8. Fluvastatina [inn-spanish]
9. Cranoc
10. Chebi:5136
11. Chembl350239
12. Fluvastatin (inn)
13. (e,3s,5r)-7-[3-(4-fluorophenyl)-1-propan-2-ylindol-2-yl]-3,5-dihydroxyhept-6-enoic Acid
14. 4l066368as
15. Fluvastatin [inn]
16. (-)-3s,5r-fluvastatin Sodium Salt
17. Xu-62320
18. Fluvas
19. Xu 62-320
20. (3s,5r,6e)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1h-indol-2-yl]-3,5-dihydroxyhept-6-enoic Acid
21. Fluvastatin [inn:ban]
22. Xu 62320
23. Unii-4l066368as
24. Nsc-758896
25. (+-)-fluvastatin
26. Fluvas (tn)
27. (3s,5r)-fluvastatin
28. Fluvastatin [mi]
29. Prestwick3_000859
30. Fluvastatin [vandf]
31. Rac-(3r,5s)-fluvastatin
32. Schembl2847
33. Schembl2849
34. Bspbio_000877
35. Fluvastatin [who-dd]
36. Bidd:gt0839
37. (-)-(3s,5r)-fluvastatin
38. (3s,5r)-(-)-fluvastatin
39. Bpbio1_000965
40. Dtxsid2020636
41. Chebi:38561
42. Chebi:94603
43. Hsdb 8366
44. 6-heptenoic Acid, 7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1h-indol-2-yl)- 3,5-dihydroxy-, (3r,5s,6e)-rel-
45. Zinc1530639
46. Bdbm50248235
47. Akos015896650
48. Db01095
49. Nsc 758896
50. (3s,5r,e)-7-(3-(4-fluorophenyl)-1-isopropyl-1h-indol-2-yl)-3,5-dihydroxyhept-6-enoic Acid
51. Ncgc00164604-10
52. C07014
53. D07983
54. Brd-k03602135-236-02-1
55. Brd-k39716612-236-01-1
56. (3s,5r,6e)-7-[3-(4-fluorophenyl)-1-isopropyl-1h-indol-2-yl]-3,5-dihydroxyhept-6-enoic Acid
57. (3s,5r,e)-7-(3-(4-fluorophenyl)-1-isopropyl-1h-indol-2-yl)-3,5-dihydroxyhept-6-enoicacid
58. (6e)-erythro7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1h-indol-2-yl]-3,5-dihydroxyhept-6-enoic Acid
59. [r*,s*-(e)]-(+/-)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1h-indol-2-yl]-3,5-dihydroxy-6-heptenoic Acid, Monosodium Salt
60. 6-heptenoic Acid, 7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1h-indol-2-yl)- 3,5-dihydroxy-, (r*,s*-(e))-(+-)-
61. 6-heptenoic Acid, 7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1h-indol-2-yl)-3,5-dihydroxy-, (3r,5s,6e)-rel-
62. Erythro-(e)-3,5-dihydroxy-7-[3'-(4''-fluorophenyl)-1'-(1''-methylethyl)indol-2'-yl]hept-6-enoic Acid
63. Rac-(3r,5s,6e)-7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1h-indol-2-yl)-3,5-dihydroxy-6-heptenoic Acid
64. Rac-(3r,5s,6e)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1h-indol-2-yl]-3,5-dihydroxyhept-6-enoic Acid
| Molecular Weight | 411.5 g/mol |
|---|---|
| Molecular Formula | C24H26FNO4 |
| XLogP3 | 3.5 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 8 |
| Exact Mass | 411.18458647 g/mol |
| Monoisotopic Mass | 411.18458647 g/mol |
| Topological Polar Surface Area | 82.7 Ų |
| Heavy Atom Count | 30 |
| Formal Charge | 0 |
| Complexity | 590 |
| Isotope Atom Count | 0 |
| Defined Atom Stereocenter Count | 2 |
| Undefined Atom Stereocenter Count | 0 |
| Defined Bond Stereocenter Count | 1 |
| Undefined Bond Stereocenter Count | 0 |
| Covalently Bonded Unit Count | 1 |
| 1 of 4 | |
|---|---|
| Drug Name | Fluvastatin |
| PubMed Health | Fluvastatin (By mouth) |
| Drug Classes | Antihyperlipidemic |
| Drug Label | Lescol (fluvastatin sodium), is a water-soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Fluvastatin sodium is [R*,S*-(E)]-()-7-[3-(4-fluorophenyl)-1-(1-m... |
| Active Ingredient | Fluvastatin |
| Dosage Form | Tablet, extended release |
| Route | oral |
| Strength | 80mg |
| Market Status | Tentative Approval |
| Company | Mylan Pharms |
| 2 of 4 | |
|---|---|
| Drug Name | Lescol xl |
| PubMed Health | Fluvastatin (By mouth) |
| Drug Classes | Antihyperlipidemic |
| Drug Label | Lescol (fluvastatin sodium), is a water-soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Fluvastatin sodium is [R*,S*-(E)]-()-7-[3-(4-fluorophenyl)-1-(1-m... |
| Active Ingredient | Fluvastatin sodium |
| Dosage Form | Tablet, extended release |
| Route | Oral |
| Strength | 80mg |
| Market Status | Prescription |
| Company | Novartis |
| 3 of 4 | |
|---|---|
| Drug Name | Fluvastatin |
| PubMed Health | Fluvastatin (By mouth) |
| Drug Classes | Antihyperlipidemic |
| Drug Label | Lescol (fluvastatin sodium), is a water-soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Fluvastatin sodium is [R*,S*-(E)]-()-7-[3-(4-fluorophenyl)-1-(1-m... |
| Active Ingredient | Fluvastatin |
| Dosage Form | Tablet, extended release |
| Route | oral |
| Strength | 80mg |
| Market Status | Tentative Approval |
| Company | Mylan Pharms |
| 4 of 4 | |
|---|---|
| Drug Name | Lescol xl |
| PubMed Health | Fluvastatin (By mouth) |
| Drug Classes | Antihyperlipidemic |
| Drug Label | Lescol (fluvastatin sodium), is a water-soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Fluvastatin sodium is [R*,S*-(E)]-()-7-[3-(4-fluorophenyl)-1-(1-m... |
| Active Ingredient | Fluvastatin sodium |
| Dosage Form | Tablet, extended release |
| Route | Oral |
| Strength | 80mg |
| Market Status | Prescription |
| Company | Novartis |
Anticholesteremic Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors
National Library of Medicine's Medical Subject Headings. Fluvastatin. Online file (MeSH, 2016). Available from, as of November 1, 2016: https://www.nlm.nih.gov/mesh/2016/mesh_browser/MBrowser.html
Fluvastatin capsules are indicated: as an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG) and apolipoprotein B (Apo B) levels, and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb); As an adjunct to diet to reduce Total-C, LDL-C, and Apo B levels in adolescent boys and adolescent girls who are at least one year post-menarche, 10 to 16 years of age, with heterozygous familial hypercholesterolemia and the following findings are present: 1. LDL-C remains >/= 190 mg/dL or 2. LDL-C remains >/= 160 mg/dL and: there is a positive family history of premature cardiovascular disease or two or more other cardiovascular disease risk factors are present. /Included in US product label/
NIH; DailyMed. Current Medication Information for Fluvastatin Tablet (Updated: March 2016). Available from, as of November 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad8b373-0aec-4efb-8e61-3d8114b31127#i4i_section_id_5f2eb94b-4cdf-4517-9ad8-298e02fe9677
In patients with clinically evident coronary heart disease (CHD), fluvastatin capsules are indicated to: reduce the risk of undergoing coronary revascularization procedures and slow the progression of coronary atherosclerosis. /Included in US product label/
NIH; DailyMed. Current Medication Information for Fluvastatin Tablet (Updated: March 2016). Available from, as of November 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad8b373-0aec-4efb-8e61-3d8114b31127#i4i_section_id_5f2eb94b-4cdf-4517-9ad8-298e02fe9677
Fluvastatin has reduced total and LDL-cholesterol concentrations in a few patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus (diabetic dyslipidemia), renal insufficiency,cardiac or renal transplantation, or nephrotic syndrome (nephrotic hyperlipidemia). Fluvastatin also has been shown to decrease proteinuria in patients with immunoglobulin A nephropathy. Additional studies are necessary to determine the role, if any, of fluvastatin therapy in patients with these disorders. /NOT included in US product label/
American Society of Health-System Pharmacists 2016; Drug Information 2016. Bethesda, MD. 2016, p. 1849
Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with fluvastatin capsules and other drugs in this class.
NIH; DailyMed. Current Medication Information for Fluvastatin Tablet (Updated: March 2016). Available from, as of November 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad8b373-0aec-4efb-8e61-3d8114b31127#i4i_section_id_5f2eb94b-4cdf-4517-9ad8-298e02fe9677
There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including fluvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with fluvastatin sodium, promptly interrupt therapy. If an alternate etiology is not found do not restart fluvastatin sodium.
NIH; DailyMed. Current Medication Information for Fluvastatin Tablet (Updated: March 2016). Available from, as of November 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad8b373-0aec-4efb-8e61-3d8114b31127#i4i_section_id_5f2eb94b-4cdf-4517-9ad8-298e02fe9677
Fluvastatin is secreted into the breast milk of animals and because HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require treatment with fluvastatin capsules should be advised not to breastfeed their infants.
NIH; DailyMed. Current Medication Information for Fluvastatin Tablet (Updated: March 2016). Available from, as of November 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad8b373-0aec-4efb-8e61-3d8114b31127#i4i_section_id_5f2eb94b-4cdf-4517-9ad8-298e02fe9677
Fluvastatin capsules are contraindicated in women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Fluvastatin capsules may cause fetal harm when administered to pregnant women. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Fluvastatin capsules should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this drug, fluvastatin capsules should be discontinued and the patient should be apprised of the potential hazard to the fetus.
NIH; DailyMed. Current Medication Information for Fluvastatin Tablet (Updated: March 2016). Available from, as of November 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad8b373-0aec-4efb-8e61-3d8114b31127#i4i_section_id_5f2eb94b-4cdf-4517-9ad8-298e02fe9677
For more Drug Warnings (Complete) data for Fluvastatin (24 total), please visit the HSDB record page.
To be used as an adjunct to dietary therapy to prevent cardiovascular events. May be used as secondary prevention in patients with coronary heart disease (CHD) to reduce the risk of requiring coronary revascularization procedures, for reducing progression of coronary atherosclerosis in hypercholesterolemic patients with CHD, and for the treatment of primary hypercholesterolemia and mixed dyslidipidemia.
FDA Label
Fluvastatin, the first synthetically-derived HMG-CoA reductase inhibitor, is a hydrophilic, acidic, antilipemic agent used to lower cholesterol and triglyceride levels associated with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson types IIa and IIb), to slow the progression of coronary atherosclerosis in patients with CHD and as secondary prevention therapy in patients with CHD to reduce the risk of requiring coronary revascularization procedures. Although similar to lovastatin, simvastatin, and pravastatin, fluvastatin has a shorter half-life, no active metabolites, extensive protein binding, and minimal CSF penetration. Fluvastatin acts primarily in the liver. It is prepared as a racemate of two erythro enantiomers of which the 3R,5S enantiomer exerts the pharmacologic effect.
Absorption
Rapidly and almost completely absorbed (> 90%), but undergoes extensive first pass metabolism. Bioavailability is 24% (range 9-50%) when a 10 mg dose is given. The mean relative bioavailability of the extended-release tablet is 29% (range: 9% to 66%) compared to an immediate-release capsule administered under fasting conditions. When given orally, fluvastatin reaches peak concentrations (Tmax) in less than one hour. Taking the extended release tablet with a high-fat meal will delay absorption (Tmax = 6 hours) and increase bioavailability by approximately 50%. However, the maximum concentration of fluvastatin sodium extended-release tablets seen after a high fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg fluvastatin capsule.
Route of Elimination
When orally administered, fluvastatin is primarily excreted in the faces ( ~90%) as metabolites, with less than 2% present as unchanged drug. Approximately 5% was recovered in the urine.
Volume of Distribution
0.35 L/kg
Clearance
0.8 L/h/kg
107 38.1 L/h [Hypercholesterolemia patients receiving a single dose of 20 mg]
87.8 45 L/h [Hypercholesterolemia patients receiving 20 mg twice daily]
108 44.7 L/h [Hypercholesterolemia patients receiving 40 mg single]
64.2 21.1 L/h [Hypercholesterolemia patients receiving 40 mg twice daily]
/MILK/ Based on animal data, fluvastatin is present in breast milk in a 2:1 ratio (milk:plasma).
NIH; DailyMed. Current Medication Information for Fluvastatin Tablet (Updated: March 2016). Available from, as of November 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad8b373-0aec-4efb-8e61-3d8114b31127#i4i_section_id_5f2eb94b-4cdf-4517-9ad8-298e02fe9677
Following oral administration of the capsule, fluvastatin reaches peak concentrations in less than 1 hour. The absolute bioavailability is 24% (range 9% to 50%) after administration of a 10 mg dose.
NIH; DailyMed. Current Medication Information for Fluvastatin Tablet (Updated: March 2016). Available from, as of November 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad8b373-0aec-4efb-8e61-3d8114b31127#i4i_section_id_5f2eb94b-4cdf-4517-9ad8-298e02fe9677
Fluvastatin is 98% bound to plasma proteins. The mean volume of distribution (VDss) is estimated at 0.35 L/kg. At therapeutic concentrations, the protein binding of fluvastatin is not affected by warfarin, salicylic acid and glyburide.
NIH; DailyMed. Current Medication Information for Fluvastatin Tablet (Updated: March 2016). Available from, as of November 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad8b373-0aec-4efb-8e61-3d8114b31127#i4i_section_id_5f2eb94b-4cdf-4517-9ad8-298e02fe9677
Fluvastatin administered as fluvastatin sodium extended-release 80 mg tablets reaches peak concentration in approximately 3 hours under fasting conditions, after a low fat meal, or 2.5 hours after a low fat meal. The mean relative bioavailability of the extended-release tablet is approximately 29% (range: 9% to 66%) compared to that of the fluvastatin immediate-release capsule administered under fasting conditions. Administration of a high fat meal delayed the absorption (Tmax: 6 hr) and increased the bioavailability of the extended-release tablet by approximately 50%. However, the maximum concentration of fluvastatin sodium extended-release tablets seen after a high fat meal is less than the peak concentration following a single dose or twice daily dose of the 40 mg fluvastatin capsule.
NIH; DailyMed. Current Medication Information for Fluvastatin Tablet (Updated: March 2016). Available from, as of November 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad8b373-0aec-4efb-8e61-3d8114b31127#i4i_section_id_5f2eb94b-4cdf-4517-9ad8-298e02fe9677
For more Absorption, Distribution and Excretion (Complete) data for Fluvastatin (8 total), please visit the HSDB record page.
Undergoes hepatic metabolism primarily via hydroxylation of the indole ring at the 5- and 6-positions to 5-hydroxy fluvastatin and 6-hydroxy fluvastatin, respectively. N-dealkylation to N-desisopropyl fluvastatin and beta-oxidation of the side chain also occurs. Metabolized primarily by the CYP2C9 isozyme system (75%), and to a lesser extent by CYP3A4 (~20%) and CYP2C8 (~5%). Hydroxylated metabolites retain some pharmcological activity, but are present as conjugates (glucuronides and sulfates) in the blood and are rapidly eliminated via bile into feces. Both enantiomers of fluvastatin are metabolized in a similar manner. Fluvastatin also undergoes glucuronidation via UGT enzymes.
In vitro data indicate that fluvastatin metabolism involves multiple Cytochrome P450 (CYP) isozymes. CYP2C9 isoenzyme is primarily involved in the metabolism of fluvastatin (approximately 75%), while CYP2C8 and CYP3A4 isoenzymes are involved to a much less extent, i.e., approximately 5% and approximately 20%, respectively.
NIH; DailyMed. Current Medication Information for Fluvastatin Tablet (Updated: March 2016). Available from, as of November 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad8b373-0aec-4efb-8e61-3d8114b31127#i4i_section_id_5f2eb94b-4cdf-4517-9ad8-298e02fe9677
Fluvastatin is metabolized in the liver, primarily via hydroxylation of the indole ring at the 5 and 6 positions. N-dealkylation and beta-oxidation of the side-chain also occurs. The hydroxy metabolites have some pharmacologic activity, but do not circulate in the blood. Fluvastatin has two enantiomers. Both enantiomers of fluvastatin are metabolized in a similar manner.
NIH; DailyMed. Current Medication Information for Fluvastatin Tablet (Updated: March 2016). Available from, as of November 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad8b373-0aec-4efb-8e61-3d8114b31127#i4i_section_id_5f2eb94b-4cdf-4517-9ad8-298e02fe9677
Fluvastatin has known human metabolites that include 5-hydroxy-fluvastatin, 6-hydroxy-fluvastatin, and N-Deisopropyl-fluvastatin.
S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560
3 hours
The elimination half-life of fluvastatin is approximately 3 hours.
NIH; DailyMed. Current Medication Information for Fluvastatin Tablet (Updated: March 2016). Available from, as of November 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad8b373-0aec-4efb-8e61-3d8114b31127#i4i_section_id_5f2eb94b-4cdf-4517-9ad8-298e02fe9677
Fluvastatin selectively and competitively inhibits the hepatic enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is responsible for converting HMG-CoA to mevalonate, the rate-limiting step in cholesterol biosynthesis. Inhibition results in a decrease in hepatic cholesterol levels which stimulates the synthesis of LDL receptors and increases hepatic uptake of LDL cholesterol. The end result is decreased levels of plasma total and LDL cholesterol.
Fluvastatin sodium is a competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. The inhibition of cholesterol biosynthesis reduces the cholesterol in hepatic cells, which stimulates the synthesis of LDL receptors and thereby increases the uptake of LDL particles. The end result of these biochemical processes is a reduction of the plasma cholesterol concentration.
NIH; DailyMed. Current Medication Information for Fluvastatin Tablet (Updated: March 2016). Available from, as of November 4, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aad8b373-0aec-4efb-8e61-3d8114b31127#i4i_section_id_5f2eb94b-4cdf-4517-9ad8-298e02fe9677
Statins are largely used in clinics in the treatment of patients with cardiovascular diseases for their effect on lowering circulating cholesterol. Lectin-like oxidized low-density lipoprotein (LOX-1), the primary receptor for ox-LDL, plays a central role in the pathogenesis of atherosclerosis and cardiovascular disorders. We have recently shown that chronic exposure of cells to lovastatin disrupts LOX-1 receptor cluster distribution in plasma membranes, leading to a marked loss of LOX-1 function. Here we investigated the molecular mechanism of statin-mediated LOX-1 inhibition and we demonstrate that all tested statins /including fluvastatin/ are able to displace the binding of fluorescent ox-LDL to LOX-1 by a direct interaction with LOX-1 receptors in a cell-based binding assay. Molecular docking simulations confirm the interaction and indicate that statins completely fill the hydrophobic tunnel that crosses the C-type lectin-like (CTLD) recognition domain of LOX-1. Classical molecular dynamics simulation technique applied to the LOX-1 CTLD, considered in the entire receptor structure with or without a statin ligand inside the tunnel, indicates that the presence of a ligand largely increases the dimer stability. Electrophoretic separation and western blot confirm that different statins binding stabilize the dimer assembly of LOX-1 receptors in vivo. The simulative and experimental results allow us to propose a CTLD clamp motion, which enables the receptor-substrate coupling. These findings reveal a novel and significant functional effect of statins.
PMID:25950192 Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614984 Biocca S et al; Cell Cycle 14 (10): 1583-95 (2015)
Epidemiological studies suggest that statins (hydroxymethylglutaryl-CoA reductase inhibitors) could reduce the risk of Alzheimer disease. Although one possible explanation is through an effect on beta-amyloid (Abeta) metabolism, its effect remains to be elucidated. Here, we explored the molecular mechanisms of how statins influence Abeta metabolism. Fluvastatin at clinical doses significantly reduced Abeta and amyloid precursor protein C-terminal fragment (APP-CTF) levels among APP metabolites in the brain of C57BL/6 mice. Chronic intracerebroventricular infusion of lysosomal inhibitors blocked these effects, indicating that up-regulation of the lysosomal degradation of endogenous APP-CTFs is involved in reduced Abeta production. Biochemical analysis suggested that this was mediated by enhanced trafficking of APP-CTFs from endosomes to lysosomes, associated with marked changes of Rab proteins, which regulate endosomal function. In primary neurons, fluvastatin enhanced the degradation of APP-CTFs through an isoprenoid-dependent mechanism. Because our previous study suggests additive effects of fluvastatin on Abeta metabolism, we examined Abeta clearance rates by using the brain efflux index method and found its increased rates at high Abeta levels from brain. As LRP1 in brain microvessels was increased, up-regulation of LRP1-mediated Abeta clearance at the blood-brain barrier might be involved. In cultured brain microvessel endothelial cells, fluvastatin increased LRP1 and the uptake of Abeta, which was blocked by LRP1 antagonists, through an isoprenoid-dependent mechanism. Overall, the present study demonstrated that fluvastatin reduced Abeta level by an isoprenoid-dependent mechanism. ...
PMID:20472556 Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903370 Shinohara M et al; J Biol Chem 285 (29): 22091-102 (2010)
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