CERIVASTATIN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C26H34FNO5
Molecular Weight	459.5503
Optical Activity	UNSPECIFIED
Defined Stereocenters	2 / 2
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

SMILES

COCC1=C(C2=CC=C(F)C=C2)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C(N=C1C(C)C)C(C)C

InChI

InChIKey=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

HIDE SMILES / InChI

Molecular Formula	C26H34FNO5
Molecular Weight	459.5503
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	2 / 2
E/Z Centers	1
Optical Activity	UNSPECIFIED

Description

Cerivastatin (BAYCOL®) is a competitive inhibitor of HMG-CoA reductase, which is responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. The inhibition of cholesterol biosynthesis by cerivastatin reduces the level of cholesterol in hepatic cells, which stimulates the synthesis of low-density lipoprotein (LDL) receptors, thereby increasing the uptake of cellular LDL particles. The end result of these biochemical processes is a reduction of the plasma cholesterol concentration. 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 It has also been withdrawn from the Canadian market.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
HMG-CoA reductase 47	Inhibitor 8,297		5.7 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hypercholesterolemia 47	Primary		Withdrawn	BAYCOL
Mixed dyslipidemia (Fredrickson types IIa and IIb) 2	Primary		Withdrawn	BAYCOL

C_max

Value	Dose	Analyte	Population
2.31 μg/L	200 μg 1 times / day steady-state, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
3.96 μg/L	300 μg 1 times / day steady-state, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
4.41 μg/L	400 μg 1 times / day steady-state, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
1.14 μg/L	100 μg 1 times / day steady-state, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
2.15 μg/L	200 μg single, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
3.55 μg/L	300 μg single, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
4.04 μg/L	400 μg single, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
1.01 μg/L	100 μg single, oral	CERIVASTATIN SODIUM plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
12.4 μg × h/L	200 μg 1 times / day steady-state, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
21.73 μg × h/L	300 μg 1 times / day steady-state, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
24.67 μg × h/L	400 μg 1 times / day steady-state, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
6.33 μg × h/L	100 μg 1 times / day steady-state, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
11.71 μg × h/L	200 μg single, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
20.52 μg × h/L	300 μg single, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
22.45 μg × h/L	400 μg single, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
6.25 μg × h/L	100 μg single, oral	CERIVASTATIN SODIUM plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
2.74 h	200 μg 1 times / day steady-state, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
3.79 h	300 μg 1 times / day steady-state, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
5.16 h	400 μg 1 times / day steady-state, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
3.19 h	100 μg 1 times / day steady-state, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
3.08 h	200 μg single, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
4.89 h	300 μg single, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
4.23 h	400 μg single, oral	CERIVASTATIN SODIUM plasma	Homo sapiens
3.37 h	100 μg single, oral	CERIVASTATIN SODIUM plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
1%	200 μg 1 times / day steady-state, oral		CERIVASTATIN SODIUM blood	Homo sapiens

Doses

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Dose	Population	Adverse events
0.8 mg 1 times / day steady, oral Studied dose	unhealthy, 57.2 years n = 776	Disc. AE: CPK increased, Elevated liver enzymes...
0.4 mg 1 times / day steady, oral Recommended	unhealthy, 57.3 years n = 195	Disc. AE: CPK increased, Elevated liver enzymes...
0.4 mg 1 times / day steady, oral Recommended	unhealthy, adult n = 1263	Disc. AE: Rhinitis, Headache...
0.4 mg 1 times / day steady, oral Recommended	unhealthy, adult n = 2816	Disc. AE: Gastrointestinal disorders...

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AEs

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AE	Significance	Dose	Population
Arthralgia	1 patient Disc. AE	0.8 mg 1 times / day steady, oral Studied dose	unhealthy, 57.2 years n = 776
Chest pain	1 patient Disc. AE	0.8 mg 1 times / day steady, oral Studied dose	unhealthy, 57.2 years n = 776
Constipation	1 patient Disc. AE	0.8 mg 1 times / day steady, oral Studied dose	unhealthy, 57.2 years n = 776
Dyspepsia	1 patient Disc. AE	0.8 mg 1 times / day steady, oral Studied dose	unhealthy, 57.2 years n = 776
Eye pain	1 patient Disc. AE	0.8 mg 1 times / day steady, oral Studied dose	unhealthy, 57.2 years n = 776

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 699 OATP2B1 123 BSEP 402 CYP2C8 911	CYP2C8 693 P-gp 1,537 OATP1B1 406

Drug as perpetrator

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Target	Modality	Activity
CYP2C8 965	inhibitor 3,277	weak [IC50 30 uM]
OATP2B1 126	inhibitor 3,277	yes [IC50 66.2 uM]
BSEP 403	inhibitor 3,277	yes [Ki 11.4 uM]
BCRP 773	inhibitor 3,277	yes [Ki 18.1 uM]

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Drug as victim

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Target	Modality	Activity	Clinical evidence
OATP1B1 406	substrate 3,367	yes
P-gp 1,537	substrate 3,367	yes
CYP2C8 693	substrate 3,367	yes	yes (co-administration study)
CYP3A4 1,737	substrate 3,367	yes	yes (co-administration study)

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:3559	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:3559
MolPort	MolPort-003-845-726	https://www.molport.com/shop/molecule-link/MolPort-003-845-726
eMolecules	26944548	https://www.emolecules.com/cgi-bin/more?vid=26944548

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PubMed

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Title	Date	PubMed
Three-dimensional quantitative structure (3-D QSAR) activity relationship studies on imidazolyl and N-pyrrolyl heptenoates as 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) inhibitors by comparative molecular similarity indices analysis (CoMSIA).	2005 Feb 15	15686906
Prediction of genotoxicity of chemical compounds by statistical learning methods.	2005 Jun	15962942

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Patents

Sample Use Guides

In Vivo Use Guide

The starting-dose of BAYCOL® is 0.4 mg once daily in the evening regardless of previous lipid therapy. Since the maximal effect of cerivastatin is seen within 4 weeks lipid determinations should be performed at this time and the dose adjusted based upon patient response. Only patients requiring further lipid adjustment should be titrated to 0.8 mg. The dosage range is 0.2 mg to 0.8 mg. Cerivastatin may be taken with or without food.

Route of Administration: Oral

In Vitro Use Guide

Cerivastatin inhibited the membrane-bound (non-solubilized) 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase of the native microsomal fraction isolated from rat liver with a Ki value of 1.3 nM. Cerivastatin inhibited the cholesterol synthesis in the human hepatoma cell line HepG2 cells with a IC50 value of 1.0 nM.