Cerivastatin

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Cerivastatin
Cerivastatin.svg
Clinical data
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  • AU:D
Routes of
administration 		By mouth
ATC code
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Legal status
  • Withdrawn
Pharmacokinetic data
Elimination half-life 2–3 hours
Identifiers
  • (3R,5S,6E)-7-[4-(4-Fluorophenyl)-5-(methoxymethyl)-2,6-bis(propan-2-yl)pyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid
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PubChem CID
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Chemical and physical data
Formula C26H34FNO5
Molar mass 459.558 g·mol−1
3D model (JSmol)
  • O=C(O)C[C@H](O)C[C@H](O)/C=C/c1c(nc(c(c1c2ccc(F)cc2)COC)C(C)C)C(C)C
  • 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 Yes check.svgY
  • Key:SEERZIQQUAZTOL-ANMDKAQQSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Cerivastatin (INN, [1] brand names: Baycol, Lipobay) is a synthetic member of the class of statins used to lower cholesterol and prevent cardiovascular disease. It was marketed by the pharmaceutical company Bayer A.G. in the late 1990s, competing with Pfizer's highly successful atorvastatin (Lipitor). Cerivastatin was voluntarily withdrawn from the market worldwide in 2001, due to reports of fatal rhabdomyolysis.

Contents

During postmarketing surveillance, 52 deaths were reported in patients using cerivastatin, mainly from rhabdomyolysis and its resultant kidney failure. [2] Risks were higher in patients using fibrates, mainly gemfibrozil (Lopid), and in patients using the highest (0.8 mg/day) dose of cerivastatin. Bayer A.G. added a contraindication for the concomitant use of cerivastatin and gemfibrozil to the package 18 months after the drug interaction was found. [3] The frequency of deadly cases of rhabdomyolysis with cerivastatin was 16 to 80 times higher than with other statins. [4] Another 385 nonfatal cases of rhabdomyolysis were reported. This put the risk of this (rare) complication at 5-10 times that of the other statins. Cerivastatin also induced myopathy in a dose-dependent manner when administered as monotherapy, but that was revealed only after Bayer was sued and unpublished company documents were opened. [5]

Structure and reactivity

Cerivastatin consists of a fluorophenyl linked to a pyridine. The pyridine has two isopropyl groups, one methoxy group and a dihydroxyheptanoic acid side chain. The dihydroxyheptanoic acid group is the functional part of the molecule. This part will bind to the HMG-CoA reductase making it unavailable for HMG-CoA. [6] Cerivastatin is a pure synthetic drug, produced to create a more potent inhibitor of HMG-CoA reductase. Cerivastatin was the most potent inhibitor with an inhibitory constant of 0.5 μg/L, which made it already effective at a low dose. It is taken up orally as tablets, where it is combined with sodium salt. The IUPAC name is then (+)-(3R,5S,6E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethylpyridin-3-yl]-3,5-dihydroxy-6-heptenoic acid monosodium salt. [7] Cerivastatin sodium (C22H33FNO3Na) is administered orally via a tablet. The molecular weight is 481.5 g/mol. [6] It is odorless and it is soluble in water, methanol and ethanol. Under acidic circumstances, it undergoes cyclization to form pyridinolactone. [7]

Mechanism of action

Five main classes of agents can be used to treat hyperlipidemia, a condition that comes with high cholesterol levels. Those are bile acid sequestrants, nicotinic acid, fibric acid derivatives, probucol and HMG-CoA-reductase inhibitors. Cerivastatin mainly acts by competitively inhibiting HMG-CoA-reductase, which is the rate-limiting enzyme step in cholesterol biosynthesis. [8] [9] It occurs during the mevalonate pathway in the liver, where hydroxylmethylglutaryl is converted to mevalonate. Cerivastatin is a synthetic and enantiomerically pure inhibitor of the reductase, meaning it can fit into the enzyme's active site, and therefore compete with the substrate HMG-CoA, which is the native substrate for the reductase. [10] Due to the competition, the rate of mevalonate production by the enzyme is reduced. This also means that the rates subsequent biosynthesis is reduced, since less starting material is available. Eventually, this will lead to lower cholesterol levels.

The location of cholesterol biosynthesis and inhibition of HMG-CoA is of significance, since most circulating cholesterol originates from internal production, rather than the diet. If the liver cannot produce more cholesterol, the cholesterol levels in the blood will decrease. Also, HMG-CoA-reductase inhibitors cause secondary up-regulation of hepatic LDL receptors, with increased LDL-cholesterol clearance and reduction of both total and LDL cholesterol in the serum.

Metabolism

Cerivastatin is metabolized via the hepatic pathway. [11] In vitro studies with human liver cells showed that two metabolic pathways are equally important; demethylation of the benzylic methyl ether and hydroxylation at one methyl group of the 6-isopropyl substituent. [12] [13] Demethylation is catalysed by the enzymes CYP2C8 and CYP3A4, which generates a metabolite that is known as M-1 in the cerivastatin metabolite pathway. Hydroxylation is catalysed by CYP2C8, which generates the major active metabolite, M-23. [6] M-1 and M-23 are, like cerivastatin, pharmacologically active, with comparable potencies. Combination of the latter leads to another minor metabolite, that is not detectable in plasma, which is also known as M-24. Following a 0.8 mg dose of cerivastatin, the mean steady state Cmax values for cerivastatin, M-1 and M-23 were 12.7, 0.55 and 1.4 μg/L, respectively. Hence, it can be concluded that the cholesterol-lowering effect is mostly due to the cerivastatin itself.

Efficacy, toxicity and side effects

Efficacy and toxicity

The inhibitory activity of cerivastatin was compared to that of other statins, specifically lovastatin, simvastatin and pravastatin. This comparison was made by determining the IC50 values of each compound. These values were 77 nM, 66 nM and 176 nM for these statins, respectively, while the value for cerivastatin was found to be 1.1 nM. Using Dixon plots, the inhibitory constant of cerivastatin was found to be 1.3 x 10-9 M, which is over 100 times lower than the inhibitory constant of lovastatin, known to be 150 x 10-9 M. To compare cerivastatin activity to that of other statins, its IC25 value was also determined for various types of human smooth muscle cells: cells from the left internal mammary artery (HSMC), cornea fibroblasts (HCF), myoblasts from striated muscle (HM) and umbilical vein endothelial cells (HUVEC). The activity in these groups of muscle cells was compared to the activity of the statins listed above, as well as atorvastatin and fluvastatin.

The pharmacological results from cerivastatin show that it is the most active HMG-CoA-reductase inhibitor among reported statins. Due to its high enzyme affinity, it would seem to offer ultra-low dose therapy in the microgram range. However, due to its relatively severe adverse effects in comparison to other statins, its market use was discontinued.

The strengths of the available cerivastatin medicine ranged from 0.2 - 0.8 mg, resulting in an actual dose of 1.9 - 13.1 μg/kg body weight for which rhabdomyolysis has been reported. [14] Although the mechanism of the cerivastatin induced myopathy is not exactly known, [15] the risk increases with statin dose. [3] [16] [17] This risk also appears to increase among patients who received gemfibrozil [3] [18] or lovastatin [16] concomitantly, and there is a known interaction between these drugs and cerivastatin. There are 31 cerivastatin-related deaths reported in the US and a further 21 deaths worldwide. There were also 385 cases of non-fatal rhabdomyolysis reported among the estimated 700.000 users in the USA. [3] In 12 of the 31 reported deaths of cerivastatin-related rhabdomyolysis in the US the cerivastatin-gemfibrozil interaction was implicated, while in 7 of the 31 fatal cases in the US, cerivastatin was combined with lovastatin. [3] [16] The reporting rate of fatal rhabdomyolysis in association with cerivastatin monotherapy is 1.9 per million prescriptions, which is 10-50 times as high as for other statins. [16]

Adverse effects

Cerivastatin was generally found to be well tolerated, side effects being rare. Minor side effects include diarrhea, fatigue, gas, heartburn, nasal congestion and headache. Patients with alcoholic or other liver diseases were advised to use cerivastatin with caution. [19]

Related Research Articles

<span class="mw-page-title-main">Cholesterol</span> Sterol biosynthesized by all animal cells

Cholesterol is the principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.

<span class="mw-page-title-main">Statin</span> Class of drugs to lower cholesterol

Statins are a class of medications that reduce illness and mortality in people who are at high risk of cardiovascular disease.

<span class="mw-page-title-main">Mevalonate pathway</span> Series of interconnected biochemical reactions

The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are used to make isoprenoids, a diverse class of over 30,000 biomolecules such as cholesterol, vitamin K, coenzyme Q10, and all steroid hormones.

<span class="mw-page-title-main">Atorvastatin</span> Cholesterol-lowering medication

Atorvastatin is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.

<span class="mw-page-title-main">Simvastatin</span> Lipid-lowering medication

Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of heart problems in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Fluvastatin</span> Chemical compound

Fluvastatin is a member of the statin drug class, used to treat hypercholesterolemia and to prevent cardiovascular disease.

<span class="mw-page-title-main">Rosuvastatin</span> Statin medication

Rosuvastatin, sold under the brand name Crestor among others, is a statin medication, used to prevent cardiovascular disease in those at high risk and treat abnormal lipids. It is recommended to be used together with dietary changes, exercise, and weight loss. It is taken orally.

<span class="mw-page-title-main">Pravastatin</span> Cholesterol lowering medication in the statin class

Pravastatin, sold under the brand name Pravachol among others, is a statin medication, used for preventing cardiovascular disease in those at high risk and treating abnormal lipids. It is suggested to be used together with diet changes, exercise, and weight loss. It is taken by mouth.

<span class="mw-page-title-main">Lovastatin</span> Chemical compound

Lovastatin, sold under the brand name Mevacor among others, is a statin medication, to treat high blood cholesterol and reduce the risk of cardiovascular disease. Its use is recommended together with lifestyle changes. It is taken by mouth.

<span class="mw-page-title-main">HMG-CoA reductase</span> Mammalian protein found in Homo sapiens

HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. HMGCR catalyzes the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol. Normally in mammalian cells this enzyme is competitively suppressed so that its effect is controlled. This enzyme is the target of the widely available cholesterol-lowering drugs known collectively as the statins, which help treat dyslipidemia.

<span class="mw-page-title-main">Mevastatin</span> Chemical compound

Mevastatin is a hypolipidemic agent that belongs to the statins class.

<span class="mw-page-title-main">Mevalonic acid</span> Chemical compound

Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as mevalonate and is of major pharmaceutical importance. Drugs like statins stop the production of mevalonate by inhibiting HMG-CoA reductase.

<span class="mw-page-title-main">Red yeast rice</span> Type of bright reddish purple fermented rice

Red yeast rice, red rice koji, red fermented rice, red kojic rice, red koji rice, anka, or angkak, is a bright reddish purple fermented rice, which acquires its color from being cultivated with the mold Monascus purpureus. Red yeast rice is what is referred to as a "koji" in Japanese, meaning "grain or bean overgrown with a mold culture", a food preparation tradition going back to ca. 300 BC. In both the scientific and popular literature in English that draws principally on Japanese traditional use, red yeast rice is most often referred to as "red rice koji." English language articles favoring Chinese literature sources prefer the translation "red yeast rice."

<span class="mw-page-title-main">Pitavastatin</span> Chemical compound

Pitavastatin is a member of the blood cholesterol lowering medication class of statins.

<span class="mw-page-title-main">HMG-CoA</span> Chemical compound

β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzyme A, is an intermediate in the mevalonate and ketogenesis pathways. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase. The research of Minor J. Coon and Bimal Kumar Bachhawat in the 1950s at University of Illinois led to its discovery.

<span class="mw-page-title-main">Farnesyl-diphosphate farnesyltransferase</span> Class of enzymes

Squalene synthase (SQS) or farnesyl-diphosphate:farnesyl-diphosphate farnesyl transferase is an enzyme localized to the membrane of the endoplasmic reticulum. SQS participates in the isoprenoid biosynthetic pathway, catalyzing a two-step reaction in which two identical molecules of farnesyl pyrophosphate (FPP) are converted into squalene, with the consumption of NADPH. Catalysis by SQS is the first committed step in sterol synthesis, since the squalene produced is converted exclusively into various sterols, such as cholesterol, via a complex, multi-step pathway. SQS belongs to squalene/phytoene synthase family of proteins.

The discovery of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors, called statins, was a breakthrough in the prevention of hypercholesterolemia and related diseases. Hypercholesterolemia is considered to be one of the major risk factors for atherosclerosis which often leads to cardiovascular, cerebrovascular and peripheral vascular diseases. The statins inhibit cholesterol synthesis in the body and that leads to reduction in blood cholesterol levels, which is thought to reduce the risk of atherosclerosis and diseases caused by it.

<span class="mw-page-title-main">Lapaquistat</span> Chemical compound

Lapaquistat (TAK-475) is a cholesterol-lowering drug candidate that was abandoned before being marketed.

Bempedoic acid, sold under the brand name Nexletol among others, is a medication for the treatment of hypercholesterolemia.

Cardiovascular agents are drugs used to treat diseases associated with the heart or blood vessels. These medications are available for purchase only with a physician’s prescription. They include, but are not limited to, drugs that target hypertension (antihypertensives), hyperlipidemia (antihyperlipidemics) and blood clotting (blood-thinners) to reduce the risk of cardiovascular diseases.

References

  1. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 36" (PDF). World Health Organization. 1996. p. 142. Retrieved 29 November 2016.
  2. ↑ Furberg CD, Pitt B (2001). "Withdrawal of cerivastatin from the world market". Current Controlled Trials in Cardiovascular Medicine. 2 (5): 205–207. doi: 10.1186/cvm-2-5-205 . PMC   59524 . PMID   11806796.
  3. 1 2 3 4 5 Psaty BM, Furberg CD, Ray WA, Weiss NS (December 2004). "Potential for conflict of interest in the evaluation of suspected adverse drug reactions: use of cerivastatin and risk of rhabdomyolysis". JAMA. 292 (21): 2622–2631. doi:10.1001/jama.292.21.2622. PMID   15572720.
  4. ↑ Zeitlinger M, Müller M (2003). "[Clinico-pharmacologic explanation models of cerivastatin associated rhabdomyolysis]". Wiener Medizinische Wochenschrift (in German). 153 (11–12): 250–254. doi:10.1046/j.1563-258X.2003.03029.x. PMID   12879633. S2CID   38741903.
  5. ↑ Saito M, Hirata-Koizumi M, Miyake S, Hasegawa R (2005). "[Withdrawal of cerivastatin revealed a flaw of post-marketing surveillance system in the United States]". Kokuritsu Iyakuhin Shokuhin Eisei Kenkyujo Hokoku = Bulletin of National Institute of Health Sciences (in Japanese) (123): 41–45. PMID   16541751.
  6. 1 2 3 "Cerivastatin". DrugBank.
  7. 1 2 Mück W (August 2000). "Clinical pharmacokinetics of cerivastatin". Clinical Pharmacokinetics. 39 (2): 99–116. doi:10.2165/00003088-200039020-00002. PMID   10976657.
  8. ↑ Kuhlmann J, Mück W, Bischoff H, Keutz E, Llewellyn M (1998). "Cerivastatin (BAY w 6228): A Novel HMG-CoA Reductase Inhibitor". Cardiovascular Drug Reviews. 16 (3): 236–263. doi: 10.1111/j.1527-3466.1998.tb00357.x .
  9. ↑ Endo A (November 1992). "The discovery and development of HMG-CoA reductase inhibitors". Journal of Lipid Research. 33 (11): 1569–1582. doi: 10.1016/S0022-2275(20)41379-3 . PMID   1464741.
  10. ↑ Laufs U, Custodis F, Böhm M (2006). "HMG-CoA reductase inhibitors in chronic heart failure: potential mechanisms of benefit and risk". Drugs. 66 (2): 145–154. doi:10.2165/00003495-200666020-00002. PMID   16451090.
  11. ↑ Porter KE, Turner NA (July 2011). "Statins and myocardial remodelling: cell and molecular pathways". Expert Reviews in Molecular Medicine. 13: e22. doi:10.1017/S1462399411001931. PMID   21718586.
  12. ↑ Miettinen TA (March 1982). "Diurnal variation of cholesterol precursors squalene and methyl sterols in human plasma lipoproteins". Journal of Lipid Research. 23 (3): 466–473. doi: 10.1016/S0022-2275(20)38144-X . PMID   7200504.
  13. ↑ Boberg M, Angerbauer R, Fey P, Kanhai WK, Karl W, Kern A, et al. (March 1997). "Metabolism of cerivastatin by human liver microsomes in vitro. Characterization of primary metabolic pathways and of cytochrome P450 isozymes involved". Drug Metabolism and Disposition. 25 (3): 321–331. PMID   9172950.
  14. ↑ Kalaria D, Wassenaar W (October 2002). "Rhabdomyolysis and cerivastatin: was it a problem of dose?". CMAJ. 167 (7): 737. PMC   126482 . PMID   12389822.
  15. ↑ Moßhammer D, Schaeffeler E, Schwab M, Mörike K (September 2014). "Mechanisms and assessment of statin-related muscular adverse effects". British Journal of Clinical Pharmacology. 78 (3): 454–466. doi: 10.1111/bcp.12360 . PMC   4243897 . PMID   25069381.
  16. 1 2 3 4 Staffa JA, Chang J, Green L (February 2002). "Cerivastatin and reports of fatal rhabdomyolysis". The New England Journal of Medicine. 346 (7): 539–540. doi: 10.1056/nejm200202143460721 . PMID   11844864.
  17. ↑ Kalaria D, Wassenaar W (October 2002). "Rhabdomyolysis and cerivastatin: was it a problem of dose?". CMAJ. 167 (7): 737. PMC   126482 . PMID   12389822.
  18. ↑ Furberg CD, Pitt B (2001). "Withdrawal of cerivastatin from the world market". Current Controlled Trials in Cardiovascular Medicine. 2 (5): 205–207. doi: 10.1186/cvm-2-5-205 . PMC   59524 . PMID   11806796.
  19. ↑ Boberg M, Angerbauer R, Fey P, Kanhai WK, Karl W, Kern A, et al. (March 1997). "Metabolism of cerivastatin by human liver microsomes in vitro. Characterization of primary metabolic pathways and of cytochrome P450 isozymes involved". Drug Metabolism and Disposition. 25 (3): 321–331. PMID   9172950.
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