Cerivastatin

481.53

459.55

AM91H2KS67

DTXSID9022786

C65308

C - Cardiovascular system

68.65000

5.36060

1.181±0.06 g/cm3(Predicted)

646.3±55.0 °C(Predicted)

344.7ºC

1.594

In water, 2.4X10-1 mg/L at 25 deg C (est)

1.03X10-16 mm Hg at 25 deg C (est)

Henry's Law constant = 5.8X10-19 atm-cu m/mol at 25 °C (est)

pKa1 = 3.9 (carboxylic acid); pKa2 = 5.4 (pyridine)

Mol wt 481.53. Solid, specific optical rotation at 20 °C for D (sodium) line = +24.1 deg (c = 1 in ethanol) /Sodium salt/|Hydroxyl radical reaction rate constant = 9.4X10-11 cu cm/molecule-sec at 25 °C (est)

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

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.

Rhabdomyolysis, liver concerns

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.

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

Cerivastatin's former production and use as an antihyperlipoproteinemic(1-3) may have resulted in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 680(SRC), determined from a structure estimation method(2), indicates that cerivastatin is expected to have low mobility in soil(SRC). Estimated pKa values for cerivastatin are 3.9 (carboxylic acid) and 5.4 (pyridine)(3), indicating that this compound will primarily exist as an anion under neutral and basic conditions and partially as a zwiterion under acidic conditions in the environment. Volatilization of cerivastatin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.8X10-19 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Cerivastatin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-16 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data were not available(SRC, 2005).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 680(SRC), determined from a structure estimation method(2), indicates that cerivastatin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 5.8X10-19 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Estimated pKa values for cerivastatin are 3.9 (carboxylic acid) and 5.4 (pyridine)(5), indicating that this compound will primarily exist as an anion under neutral and basic conditions and partially as a zwiterion under acidic conditions in the environment. According to a classification scheme(6), an estimated BCF of 3(SRC), from an estimated log Kow of 4.8(7) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2005).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), cerivastatin, which has an estimated vapor pressure of 1.0X10-16 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase cerivastatin may be removed from the air by wet or dry deposition(SRC). Cerivastatin does contain chromophores that absorb at wavelengths >290 nm (extended conjugated hydrocarbon system) and therefore is expected to be susceptible to direct photolysis by sunlight(4).

Cerivastatin is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Cerivastatin does contain chromophores that absorb at wavelengths >290 nm (extended conjugated hydrocarbon system) and therefore is expected to be susceptible to direct photolysis by sunlight(1).

An estimated BCF of 3 was calculated for cerivastatin(SRC), using an estimated log Kow of 4.8(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of cerivastatin can be estimated to be 680(SRC). According to a classification scheme(2), this estimated Koc value suggests that cerivastatin is expected to have low mobility in soil. Estimated pKa values for cerivastatin are 3.9 (carboxylic acid) and 5.4 (pyridine)(3), indicating that this compound will primarily exist as an anion under neutral and basic conditions and partially as a zwiterion under acidic conditions in the environment.

The Henry's Law constant for cerivastatin is estimated as 5.8X10-19 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that cerivastatin is expected to be essentially nonvolatile from moist soil and water surfaces(2). Cerivastatin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-16 mm Hg(SRC), determined from a fragment constant method(3).

Cerivastatin is distributed in the breast milk at a milk to plasma concentration of 1.3 to 1.

Occupational exposure and general population exposure should be low or non-existent since cerivastatin is no longer produced or used in the US (August, 2001)(1). Exposure to cerivastatin among the general population in the past may have been limited to those administered this drug(SRC).

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

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

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.

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).

Compounds that inhibit HYDROXYMETHYLGLUTARYL COA REDUCTASES. They have been shown to directly lower CHOLESTEROL synthesis. (See all compounds classified as Hydroxymethylglutaryl-CoA Reductase Inhibitors.)

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.

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.

2-3 hours|Elimination: 2 to 3 hours

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/

/SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

/SIGNS AND SYMPTOMS/ ... The benefits of combined therapy with any statin should be carefully weighed against the risk of myopathy. The myopathy syndrome is characterized by intense myalgia, first in the arms and thighs and then in the entire body (similar to flu-related myalgia) along with fatigue. The symptoms progress as long as patients continue to take the drug or drugs that induce the myopathy. Myoglobinuria and renal failure have been reported. Serum creatine kinase (CK) levels in affected patients typically are 10-fold higher than the upper limit of normal. /Statins/|/SIGNS AND SYMPTOMS/ Rhabdomyolysis ... with or without acute renal failure secondary to myoglobinuria has occurred rarely with all statins. Fatalities secondary to rhabdomyolysis also have been reported in patients receiving statin therapy. As of June 2001, fatal rhabdomyolysis was reported in 6, 31, 0, 19, 3, or 14 of patients receiving atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, or simvastatin, respectively. /HMG-CoA reductase inhibitors/

6-Heptenoic acid, 7-(4-(4-fluorophenyl)-5-(methoxymethyl)-2,6-bis(1-methylethyl)-3-pyridinyl)-3,5-dihydroxy-, monosodium salt, (S-(R*,S*-(E)))-

Trade name (sodium salt): Baycol (Bayer, Smith Kline Beecham), Lipobay (Bayer), Zenas (Fournier)

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients