HMG-CoA reductase (Ki = 1.3 nM/L)

Treatment with cerivastatin (5–50 ng/mL; 3 days; MDA-MB-231 cells) reduced MDA-MB-231 cell proliferation in a dose-dependent manner, with up to 40% reduction observed at 25 ng/mL [1]. After 36 hours of treatment, cerivastatin (25 ng/mL; 18–36 hours; MDA-MB-231 cells) induced cell cycle arrest in the G1/S phase. At shorter incubation durations (18 hours), this standstill was not seen [1]. The administration of cerivastatin (25 ng/mL; 18 hours; MDA-MB-231 cells) significantly raises the levels of p21Waf1/Cip1 [1]. In MDA-MB-231 cells, cerivastatin administration (25 ng/mL; 12 hours) enhances p21 transcripts [1]. Matrigel-mediated MDA-MB-231 cell invasion is inhibited by ciprivastatin (10–25 ng/mL; 18 hours) [1]. Cerivastatin (25 ng/mL; 18–36 hours) causes morphological alterations and delocalizes Ras and RhoA from the cell membrane to the cytoplasm [1]. In a RhoA inhibition-dependent manner, cerivastatin (25 ng/mL; 4-36 hours) promotes NFκB inactivation, which leads to a decrease in the expression of urokinase and metalloproteinase 9, and an increase in IκB concurrently [1].

Cerivastatin is readily absorbed and reaches peak plasma concentrations one to three hours after oral treatment. Cerivastatin has a 2-4 hour half-life of elimination in the circulation and is highly bound to plasma proteins (99.5%). Three polar metabolites are primarily produced by the liver's metabolism of cerivastatin. The third metabolite is inert, and the other two are active but not as active as the original medication. All of the metabolites' plasma concentrations were noticeably lower than the parent drug's. While practically no parent compound is expelled, metabolites are removed through urine (20–25%) and feces (66-73%) [2].

Cell proliferation assay[1]
Cell Types: MDA-MB-231 Cell
Tested Concentrations: 5 ng/mL, 10 ng/mL, 25 ng/mL, 50 ng/mL
Incubation Duration: 3 days
Experimental Results: Induction of MDA-MB-231 cells of cell proliferation.

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Cell cycle analysis [1]
Cell Types: MDA-MB-231 Cell
Tested Concentrations: 25 ng/mL
Incubation Duration: 18 hrs (hours), 36 hrs (hours)
Experimental Results: Induced cell cycle arrest in G 1/S phase.

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Western Blot Analysis[1]
Cell Types: MDA-MB-231 Cell
Tested Concentrations: 25 ng/mL
Incubation Duration: 18 hrs (hours)
Experimental Results: A significant increase in p21Waf1/Cip1 levels was induced.

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RT-PCR[1]
Cell Types: MDA-MB-231 Cell
Tested Concentrations: 25 ng/mL
Incubation Duration: 12 hrs (hours)
Experimental Results: Increased p21Waf1/Cip1 mRNA levels.

Reduction of serum cholesterol, most notably low-density lipoprotein cholesterol is associated with reductions in cardiovascular morbidity and mortality. Statins have been shown to effectively reduce low-density lipoprotein cholesterol via inhibition of the hydroxymethyl-coenzyme A (HMG-CoA) reductase. Cerivastatin is the most potent HMG-CoA reductase inhibitor currently under study in the United States. METHODS AND RESULTS: A parallel group, randomized, placebo-controlled, double-blind, multicenter study was conducted to compare the efficacy and safety of three different dosing regimens of 0.2 mg/day of cerivastatin, a new HMG-CoA reductase inhibitor, in patients with hypercholesterolemia. After a 10-week diet-placebo lead-in period, 319 patients with low-density lipoprotein cholesterol >160 mg/dL were randomized to 4 weeks of treatment with one of the following regimens: cervastatin 0.1 mg twice daily, cerivastatin 0.2 mg once daily with the evening meal, cerivastatin 0.2 mg once daily at bedtime or placebo. All three active treatment groups produced statistically significant (P <.05) changes compared to aseline and placebo in total cholesterol (0.1 mg twice daily \_18.9%; 0.2 mg once daily with the evening meal: \_21.9%; 0.2 mg once daily at bedtime: \_22.1%; placebo: 0.0%), low-density lipoprotein cholesterol (0.1 mg twice daily: \_25.7%; 0.2 mg once daily with the evening meal: \_29.4%; 0.2 mg once daily at bedtime: \_30.4%; placebo: 1.4%) and high-density lipoprotein cholesterol (0.1 mg twice daily: 5.3%; 0.2 mg once daily with the evening meal: baseline and placebo, were also reduced by all active treatments (0.1 mg twice daily: \_11.6% [P =.05]; 0.2 mg once daily with the evening meal: \_11.6% [P =.05]; and 0.2 mg at bedtime: \_10.9% [P =.07]). The percentage change in total cholesterol and low-density lipoprotein cholesterol after 4 weeks of therapy for the once-daily cerivastatin groups was statistically significantly greater (P <.05) than the cerivastatin twice daily regimen. A treatment responser was seen by 1 week of therapy and was maximal by 3 weeks. The drug was well tolerated in all three dosing regimens and resulted in no significant increase in biochemical or clinical side effects compared to placebo. CONCLUSION: Cerivastatin is a novel, highly potent, well-tolerated HMG-CoA reductase inhibitor that produces low-density lipoprotein cholesterol reductions of approximately 30% when administered at 0.2 mg once a day in the evenings.[2]

Absorption, Distribution and Excretion
The mean absolute oral bioavailability 60% (range 39 - 101%).
Protein binding: Very high (> 99%) (80% to albumin)
Bioavailability 60% (range 39 to 10
Elimination: Fecal (biliary): 70%. Renal: 24%
Time to peak concentration: Approximately 2.5 hours
For more Absorption, Distribution and Excretion (Complete) data for CERIVASTATIN (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic. Biotransformation pathways for cerivastatin in humans include the following: demethylation of the benzylic methyl ether to form Ml and hydroxylation of the methyl group in the 6'-isopropyl moiety to form M23.
Administered in active (open acid) form. Biotransformation by demethylation and hydroxylation. Certain metabolites (M1 and M23) are pharmacologically active with relative potency of 50% and 100% of the parent compound, respectively.
Cerivastatin may be metabolized by both CYP3A4 and CYP2C8; however the drug appears to demonstrate higher affinity for the latter enzyme. /HMG-CoA reductase inhibitors/
Cerivastatin has known human metabolites that include (E)-7-[4-(4-Fluorophenyl)-5-(hydroxymethyl)-2,6-di(propan-2-yl)pyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid and (E)-7-[4-(4-Fluorophenyl)-6-(1-hydroxypropan-2-yl)-5-(methoxymethyl)-2-propan-2-ylpyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid.

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Biological Half-Life
2-3 hours
Elimination: 2 to 3 hours

Protein Binding
More than 99% of the circulating drug is bound to plasma proteins (80% to albumin).

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Interactions
Concurrent use of /azole antifungals, cyclosporine, gemfibrozil, other fibrates, immunosuppressants, macrolide antibiotics or niacin/ with cerivastatin ... is contraindicated, due to rhabdomyolysis and associated renal failure.
Concurrent use /with cholestyramine or colestipol/ may decrease the bioavailability of HMG-CoA reductase inhibitors; therefore, when these agents are used with HMG-CoA reductase inhibitors for therapeutic advantage, it is recommended that the HMG-CoA reductase inhibitor be given 2 to 4 hours after cholestyramine or colestipol.
The concomitant use of cerivastatin and gemfibrozil is contraindicated due to the potential for developing rhabdomyolysis. /HMG-CoA reductase inhibitors/
Myopathy and/or rhabdomyolysis has developed in some patients receiving cyclosporine concomitantly with certain statins. Although the mechanism of the interaction has not been fully elucidated, it has been suggested that this adverse effect probably results from cyclosporine-induced inhibition of statin metabolism (by the cytochrome P450 isoenzyme CYP3A4). Concomitant administration of cyclosporine and cerivastatin has resulted in an increase of threefold to fivefold in plasma concentration of the antilipemic. /HMG-CoA reductase inhibitors/
For more Interactions (Complete) data for CERIVASTATIN (9 total), please visit the HSDB record page.

[1]. Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines: an in vitro study. Carcinogenesis. 2001 Aug;22(8):1139.

[2]. Cerivastatin, a New Potent Synthetic HMG Co-A Reductase Inhibitor: Effect of 0.2 mg Daily in Subjects With Primary Hypercholesterolemia. J Cardiovasc Pharmacol Ther. 1997 Jan;2(1):7-16.

[3]. Withdrawal of cerivastatin from the world market. Curr Control Trials Cardiovasc Med. 2001;2(5):205-207.

Cerivastatin is (3R,5S)-3,5-dihydroxyhept-6-enoic acid in which the (7E)-hydrogen is substituted by a 4-(4-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)pyridin-3-yl group. Formerly used (as its sodium salt) to lower cholesterol and prevent cardiovascular disease, it was withdrawn from the market worldwide in 2001 following reports of a severe form of muscle toxicity. It is a member of pyridines, a dihydroxy monocarboxylic acid and a statin (synthetic). It is a conjugate acid of a cerivastatin(1-).
On August 8, 2001 the U.S. Food and Drug Administration (FDA) announced that Bayer Pharmaceutical Division voluntarily withdrew Baycol from the U.S. market, due to reports of fatal rhabdomyolysis, a severe adverse reaction from this cholesterol-lowering (lipid-lowering) product. It has also been withdrawn from the Canadian market.
Cerivastatin is a synthetic lipid-lowering agent. Cerivastatin competitively inhibits hepatic hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate, a key step in cholesterol synthesis. This agent lowers plasma cholesterol and lipoprotein levels, and modulates immune responses by suppressing major histocompatibility complex II on interferon gamma-stimulated, antigen-presenting cells such as human vascular endothelial cells. Muscle toxicity (myopathy and rhabdomyolysis) precludes the clinical use of this agent.

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Drug Indication
Used as an adjunct to diet for the reduction of elevated total and LDL cholesterol levels in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Types IIa and IIb) when the response to dietary restriction of saturated fat and cholesterol and other non-pharmacological measures alone has been inadequate.
FDA Label

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Mechanism of Action
Cerivastatin competitively inhibits hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the hepatic enzyme responsible for converting HMG-CoA to mevalonate. As mevalonate is a precursor of sterols such as cholesterol, this results in a decrease in cholesterol in hepatic cells, upregulation of LDL-receptors, and an increase in hepatic uptake of LDL-cholesterol from the circulation.
When statins are administered with fibrates or niacin, the myopathy is probably caused by an enhanced inhibition of skeletal muscle sterol synthesis (a pharmacodynamic interaction). /Statins/
Statins are antilipemic agents that competitively inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid, an early precursor of cholesterol. These agents are structurally similar to HMG-CoA and produce selective, reversible, competitive inhibition of HMG-CoA reductase. The high affinity of statins for HMG-CoA reductase may result from their binding to 2 separate sites on the enzyme. /HMG-CoA reductase inhibitors/

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Therapeutic Uses
Hydroxymethyglutaryl-CoA Reductase Inhibitors
MEDICATION: Antihyperlipoproteinemic
FDA announced on August 8, 2001 that Bayer Pharmaceutical Division is voluntarily withdrawing Baycol (cerivastatin) from the U.S. market because of reports of sometimes fatal rhabdomyolysis, a severe muscle adverse reaction from this cholesterol-lowering (lipid-lowering) product. The FDA agrees with and supports this decision.
Antiprotozoal and antibacterial activity against trichomonads and amebae

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Drug Warnings
FDA announced on August 8, 2001 that Bayer Pharmaceutical Division is voluntarily withdrawing Baycol (cerivastatin) from the U.S. market because of reports of sometimes fatal rhabdomyolysis, a severe muscle adverse reaction from this cholesterol-lowering (lipid-lowering) product. The FDA agrees with and supports this decision.
FDA Pregnancy Risk Category: X /CONTRAINDICATED IN PREGNANCY. Studies in animals or humans, or investigational or post-marketing reports, have demonstrated positive evidence of fetal abnormalities or risk which clearly outweights any possible benefit to the patient./
Cerivastatin (Baycol) ... should be taken at bedtime and several hours after a dose of a bile-acid sequestrant.
... The occurrence of myopathy increases when statin doses greater than 25% of maximum ... are used with niacin. /Statins/
For more Drug Warnings (Complete) data for CERIVASTATIN (17 total), please visit the HSDB record page.

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Pharmacodynamics
Cerivastatin, a competitive HMG-CoA reductase inhibitor effective in lowering LDL cholesterol and triglycerides, is used to treat primary hypercholesterolemia and mixed dyslipidemia (Fredrickson types IIa and IIb).

C26H34FNO5

459.56

441.232

C, 67.95; H, 7.46; F, 4.13; N, 3.05; O, 17.41

145599-86-6

Cerivastatin sodium;143201-11-0

446156

Typically exists as solid at room temperature

1.181 g/cm3

646.3ºC at 760 mmHg

344.7ºC

0mmHg at 25°C

1.594

5.36

3

7

11

33

620

2

O=C(C[C@@H](C[C@@H](/C=C/C1=C(C(C)C)N=C(C(C)C)C(COC)=C1C1=CC=C(F)C=C1)O)O)[O-]

SEERZIQQUAZTOL-ANMDKAQQSA-N

InChI=1S/C26H34FNO5/c1-15(2)25-21(11-10-19(29)12-20(30)13-23(31)32)24(17-6-8-18(27)9-7-17)22(14-33-5)26(28-25)16(3)4/h6-11,15-16,19-20,29-30H,12-14H2,1-5H3,(H,31,32)/b11-10+/t19-,20-/m1/s1

(E,3R,5S)-7-[4-(4-Fluorophenyl)-5-(methoxymethyl)-2,6-di(propan-2-yl)pyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid

Cerivastatin; Baycol; BAY-w-6228; BAY-w 6228; cerivastatin; 145599-86-6; cerivastatin acid; Lipobay; AM91H2KS67; CHEBI:3558; Cerivastatin (INN); (3R,5S,6E)-7-(4-(4-Fluorophenyl)-5-(methoxymethyl)-2,6-bis(1-methylethyl)-3-pyridinyl)-3,5-dihydroxy-6-heptenoic acid; BAY-w6228; Cerivastatin Sodium; Rivastatin; Lipobay

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)