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Drug

D0111 | Simvastatin

Molecular Formula C25H38O5
Molecular Weight 418.6
Structure
State solid
Volume of distribution Simvastatin can cross the blood-brain-barrier.
Route of elimination Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces.
Protein binding Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins.
Half life 3 hours
Absorption Absorption of simvastatin, estimated relative to an intravenous reference dose, in each of two animal species tested, averaged about 85% of an oral dose. In animal studies, after oral dosing, simvastatin achieved substantially higher concentrations in the liver than in non-target tissues. However, because simvastatin undergoes extensive first-pass metabolism, the availability of the drug in the systemic is low. Peak plasma concentration occurs 1.3 - 2.4 hours after administration.
Trade names Zocor
Description statin; Hypolipidemics; lipid-lowering drug; competitively inhibit the enzyme hydroxymethylglutaryl-coenzyme A (HMG-CoA) Reductase

A

C

C10BX04 Simvastatin, acetylsalicylic acid and ramipril


[C10BX] HMG CoA reductase inhibitors, other combinations


[C10B] LIPID MODIFYING AGENTS, COMBINATIONS


[C10] LIPID MODIFYING AGENTS


[C] Cardiovascular system

C10BX01 Simvastatin and acetylsalicylic acid


[C10BX] HMG CoA reductase inhibitors, other combinations


[C10B] LIPID MODIFYING AGENTS, COMBINATIONS


[C10] LIPID MODIFYING AGENTS


[C] Cardiovascular system

C10BA04 Simvastatin and fenofibrate


[C10BA] HMG CoA reductase inhibitors in combination with other lipid modifying agents


[C10B] LIPID MODIFYING AGENTS, COMBINATIONS


[C10] LIPID MODIFYING AGENTS


[C] Cardiovascular system

C10BA02 Simvastatin and ezetimibe


[C10BA] HMG CoA reductase inhibitors in combination with other lipid modifying agents


[C10B] LIPID MODIFYING AGENTS, COMBINATIONS


[C10] LIPID MODIFYING AGENTS


[C] Cardiovascular system

C10AA01 Simvastatin


[C10AA] HMG CoA reductase inhibitors


[C10A] LIPID MODIFYING AGENTS, PLAIN


[C10] LIPID MODIFYING AGENTS


[C] Cardiovascular system

A10BH51 Sitagliptin and simvastatin


[A10BH] Dipeptidyl peptidase 4 (DPP-4) inhibitors


[A10B] BLOOD GLUCOSE LOWERING DRUGS, EXCL. INSULINS


[A10] DRUGS USED IN DIABETES


[A] Alimentary tract and metabolism

Toxicity Dose Time Species Model Method Action Positive criterion Reference
OPENING OF PERMEABILITY TRANSITION PORE (PTP) 10 µM 1 hour Human HepG2 High-content screening assay Decrease MEC 306
MEMBRANE POTENTIAL 76.5 µM 30 mins mouse liver mitochondria Rh123 fluorescence (excitation 485 nm, emission 535 nm) are recorded using a fluorescence multi-well plate reader (mCICCP (20 µM) treatments was considered as the 100% baseline for ΔΨm loss) decrease EC20 36
MEMBRANE POTENTIAL 50 µM 1 hour Human HepG2 High-content screening assay Decrease MEC 306
RESPIRATION 1.6 µM 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Rotenone (2µM) was used as 100% baseline for complex I inhibition. decrease EC20 36
RESPIRATION ND 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Oligomycin A (1µM) was used as 100% baseline for complex II inhibition. Negative EC20 36
ELECTRON TRANSPORT CHAIN 50 μM bovine heart mitochondria Measurement of complex I activity decrease p < 0.01 3
ELECTRON TRANSPORT CHAIN 50 μM bovine heart mitochondria Measurement of complex II + III activity decrease p < 0.001 3
ELECTRON TRANSPORT CHAIN 50 μM bovine heart mitochondria Measurement of complex II + III activity decrease p < 0.001 3
ELECTRON TRANSPORT CHAIN 50 μM bovine heart mitochondria Measurement of complex IV activity decrease p < 0.001 3
ELECTRON TRANSPORT CHAIN 50 μM bovine heart mitochondria Measurement of complex V activity decrease p < 0.001 3
ELECTRON TRANSPORT CHAIN decrease 7
ELECTRON TRANSPORT CHAIN 100uM C2C12 myoblasts Measured ubiquinol:cytochrome c oxidoreductase activity in broken C2C12 mitochondria after acute statin exposure at a fixed concentration for all compounds. The lactone forms of the indicated statins were included in the assay medium at their cytotoxic EC50 concentration for measurement of their effect on the catalytic capacity. decrease 180
ELECTRON TRANSPORT CHAIN 200uM bovine heart mitochondria Reduction of the CIII cytochromes c1 and b was determined spectrophotometrically in bovine heart mitochondria. affect p < 0.01 180
S,N-GLYCEROPHOSPHATE SHUTTLE C2C12 myoblasts affect 180
SWELLING 173.2 µM 30 mins mouse liver mitochondria swelling assay: Absorbance at 545 nm using a fluorescence multi-well plate reader (CaCl2 (50 µM) was considered as the 100% baseline for the swelling ) increase EC20 36
ROS PRODUCTION 5 µM 1 hour Human HepG2 High-content screening assay Increase MEC 306
MITOCHONDRIAL DNA depletion 197

Target Dose Time Species Model Method Action Positive criterion Reference
NADH:ubiquinone reductase 50 μM bovine heart mitochondria Measurement of complex I activity inhibitor p < 0.01 3
NADH:ubiquinone reductase inhibitor 7
NADH:ubiquinone reductase 1.6 µM 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Rotenone (2µM) was used as 100% baseline for complex I inhibition. inhibit EC20 36
Succinate dehydrogenase 50 μM bovine heart mitochondria Measurement of complex II + III activity inhibitor p < 0.001 3
Succinate dehydrogenase ND 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Oligomycin A (1µM) was used as 100% baseline for complex II inhibition. Negative EC20 36
Quinol--cytochrome-c reductase 50 μM bovine heart mitochondria Measurement of complex II + III activity inhibitor p < 0.001 3
Quinol--cytochrome-c reductase 100uM C2C12 myoblasts Measured ubiquinol:cytochrome c oxidoreductase activity in broken C2C12 mitochondria after acute statin exposure at a fixed concentration for all compounds. The lactone forms of the indicated statins were included in the assay medium at their cytotoxic EC50 concentration for measurement of their effect on the catalytic capacity. inhibitor 180
Qo site (Qp site or ubiquinol oxidation site) 200uM bovine heart mitochondria Reduction of the CIII cytochromes c1 and b was determined spectrophotometrically in bovine heart mitochondria. inhibitor p < 0.01 180
Cytochrome c oxidase 50 μM bovine heart mitochondria Measurement of complex IV activity inhibitor p < 0.001 3
ATP synthase 50 μM bovine heart mitochondria Measurement of complex V activity inhibitor p < 0.001 3
Glycerol-3-phosphate dehydrogenase, mitochondrial C2C12 myoblasts inhibitor 180
Reactive oxygen species 5 µM 1 hour Human HepG2 High-content screening assay increase MEC 306
Cytochrome c > 200 µM 30 mins mouse liver mitochondria Cytochrome c release was evaluated using ELISA kit ( 20 µg/ml Alamethicin was used as 100% baseline) release EC20 36

Pictogram Signal Statements Precautionary Statement Codes
Danger

Aggregated GHS information provided by 187 companies from 23 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.


Reported as not meeting GHS hazard criteria by 2 of 187 companies. For more detailed information, please visit ECHA C&L website


Of the 22 notification(s) provided by 185 of 187 companies with hazard statement code(s):


H302 (26.49%): Harmful if swallowed [Warning Acute toxicity, oral]


H315 (57.3%): Causes skin irritation [Warning Skin corrosion/irritation]


H317 (25.41%): May cause an allergic skin reaction [Warning Sensitization, Skin]


H351 (26.49%): Suspected of causing cancer [Warning Carcinogenicity]


H360 (10.81%): May damage fertility or the unborn child [Danger Reproductive toxicity]


H361 (28.65%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]


H362 (11.89%): May cause harm to breast-fed children [Reproductive toxicity, effects on or via lactation]


H372 (18.92%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]


H373 (25.41%): Causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]


H411 (91.35%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]


Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.


 P201, P202, P260, P261, P263, P264, P270, P272, P273, P280, P281, P301+P312, P302+P352, P308+P313, P314, P321, P330, P332+P313, P333+P313, P362, P363, P391, P405, and P501; (The corresponding statement to each P-code can be found at the GHS Classification page.)

Organism Test type Route Dose (normalized dose) Effect Source
rat LD50 oral 4438mg/kg (4438mg/kg) Oyo Yakuri. Pharmacometrics. Vol. 39, Pg. 95, 1990.
rat LD50 intraperitoneal 705mg/kg (705mg/kg) Oyo Yakuri. Pharmacometrics. Vol. 39, Pg. 95, 1990.
mouse LD50 oral 3gm/kg (3000mg/kg) Oyo Yakuri. Pharmacometrics. Vol. 39, Pg. 95, 1990.
dog LD50 oral > 5gm/kg (5000mg/kg) Oyo Yakuri. Pharmacometrics. Vol. 39, Pg. 95, 1990.
mouse LD50 subcutaneous 1009mg/kg (1009mg/kg) behavioral: muscle contraction or spasticity) Oyo Yakuri. Pharmacometrics. Vol. 39, Pg. 95, 1990.
women LDLo oral 108mg/kg/77W- (108mg/kg) Australian and New Zealand Journal of Medicine. Vol. 25, Pg. 745, 1995.
rat LD50 subcutaneous 672mg/kg (672mg/kg) behavioral: muscle contraction or spasticity) Oyo Yakuri. Pharmacometrics. Vol. 39, Pg. 95, 1990.
mouse LD50 intraperitoneal 798mg/kg (798mg/kg) Oyo Yakuri. Pharmacometrics. Vol. 39, Pg. 95, 1990.
women TDLo oral 2800ug/kg/7D- (2.8mg/kg) Medical Journal of Australia. Vol. 155, Pg. 61, 1991.

  • Acute coronary syndrome

  • Alcohol abuse

  • Alcoholism

  • Angina pectoris

  • Arteriosclerosis

  • Arteriosclerosis coronary artery

  • Blood cholesterol increased

  • Blood triglycerides increased

  • Blood triglycerides normal

  • Cardiac failure congestive

  • Cardiovascular disorder

  • Carotid artery disease

  • Cerebrovascular accident

  • Cerebrovascular disorder

  • Coronary artery disease

  • Diabetes mellitus

  • Dyslipidaemia

  • Foetor hepaticus

  • Hepatocellular injury

  • High density lipoprotein decreased

  • Hypercholesterolaemia

  • Hypertension

  • Hypothyroidism

  • Lipid metabolism disorder

  • Liver disorder

  • Low density lipoprotein increased

  • Menarche

  • Myocardial infarction

  • Nephrotic syndrome

  • Obstruction

  • Peripheral vascular disorder

  • Premature menopause

  • Skin ulcer

  • Type II hyperlipidaemia

  • Type IIb hyperlipidaemia

  • Type IV hyperlipidaemia

  • Arthralgia (0.001)

  • Gastrointestinal disorder (0.005)

  • Abdominal pain

  • Asthenia

  • Atrial fibrillation

  • Bronchitis

  • Cataract

  • Constipation

  • Dermatitis

  • Diabetes mellitus

  • Diarrhoea

  • Dyspepsia

  • Eczema

  • Endocrine disorder

  • Flatulence

  • Gastritis

  • Gastrointestinal pain

  • Headache

  • Infection

  • Insomnia

  • Musculoskeletal discomfort

  • Musculoskeletal disorder

  • Myalgia

  • Nausea

  • Oedema

  • Pruritus

  • Rash

  • Regurgitation

  • Sinusitis

  • Swelling

  • Upper respiratory tract infection

  • Vertigo

    • (+)-Simvastatin (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-Hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyly-2,2-dimethyl butanoate (1S,3R,7S,8S,8aR)-8-(2-((2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbu
    (1S,3R,7S,8S,8aR)-8-(2-((2R,4R)-4-Hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate
    (1S,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate 2,2-Dimethylbutanoic acid (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester 2,2-Dimethylbutyric acid, 8-ester with (4R,6R)-6-(2-((1S,2S,6R,8S,8aR)-1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl)ethyl)tetrahydro-4-hydroxy-2H-pyran-2-one
    28049-EP2269989A1 28049-EP2269990A1 28049-EP2270011A1
    28049-EP2270505A1 28049-EP2272825A2 28049-EP2272841A1
    28049-EP2277865A1 28049-EP2280001A1 28049-EP2280006A1
    28049-EP2281813A1 28049-EP2284158A1 28049-EP2287165A2
    28049-EP2287166A2 28049-EP2292620A2 28049-EP2295406A1
    28049-EP2295409A1 28049-EP2295417A1 28049-EP2295422A2
    28049-EP2298731A1 28049-EP2298742A1 28049-EP2298745A1
    28049-EP2298769A1 28049-EP2298772A1 28049-EP2298776A1
    28049-EP2298779A1 28049-EP2301923A1 28049-EP2301931A1
    28049-EP2301936A1 28049-EP2305219A1 28049-EP2305648A1
    28049-EP2308839A1 28049-EP2308878A2 28049-EP2314588A1
    79902-63-9 8-[2-((2R,4R)-4-hydroxy-6-oxo(2H-3,4,5-trihydropyran-2-yl))ethyl](1S,7S,8S,3R, 8aR)-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthyl 2,2-dimethylbutanoate 902S639
    96639-EP2287163A1 96639-EP2305678A1 99548-EP2270011A1
    99548-EP2298779A1 99548-EP2301923A1 99548-EP2301931A1
    AB00053395-07 AB00053395-08 AB00053395-10
    AB00053395_11 AB00053395_13 AB0069097
    AC-1530 AGG2FN16EV AKOS005111006
    AKOS015842733 ARONIS24119 AT-7048
    BBL024390 BCBcMAP01_000007 BDBM50139181
    BIDD:GT0769 BPBio1_001001 BRD-K22134346-001-05-8
    BRD-K22134346-001-11-6 BRD-K22134346-001-15-7 BRN 4768037
    BSPBio_000909 BSPBio_002337 Butanoic acid, 2,2-dimethyl-, (1S,3R,7S,8S,*aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-((2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl ester
    Butanoic acid, 2,2-dimethyl-, (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-((2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl ester Butanoic acid, 2,2-dimethyl-, (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester Butanoic acid, 2,2-dimethyl-, 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthalenyl ester, (1S-(1alpha,3alpha,7beta,8beta(2S*,4S*),8abeta))-
    C25H38O5 CAS-79902-63-9 CCG-39069
    CCRIS 7558 CHEBI:9150 CHEMBL1064
    CPD000718785 CS-2269 Certified Reference Material
    Cholestat Coledis Colemin
    Corolin D00434 DB00641
    DRG-0320 DSSTox_CID_3581 DSSTox_GSID_23581
    DSSTox_RID_77090 DTXSID0023581 Denan
    DivK1c_006991 Eucor GTPL2955
    HMS1570N11 HMS1922H13 HMS2089D12
    HMS2093E06 HMS2097N11 HMS2231N22
    HMS3259B12 HMS3412P08 HMS3676P08
    HMS3714N11 HSDB 7208 HY-17502
    InChI=1/C25H38O5/c1-6-25(4,5)24(28)30-21-12-15(2)11-17-8-7-16(3)20(23(17)21)10-9-19-13-18(26)14-22(27)29-19/h7-8,11,15-16,18-21,23,26H,6,9-10,12-14H2,1-5H3/t15-,16-,18+,19+,20-,21-,23-/m0/s1 J10128 KBio1_001935
    KBio2_002197 KBio2_004765 KBio2_007333
    KBio3_001557 KBioGR_001244 KBioSS_002197
    KS-1113 Kolestevan L 644128-000U
    LS-46264 Labistatin Lipex
    Lipinorm Lipovas Lodales
    MCULE-8390617062 MFCD00072007 MK 0733
    MK 733 MK-0733 MK-733
    MLS001304029 MLS001333077 MLS001333078
    MLS002154038 MLS006011866 MRF-0000729
    Medipo Modutrol NC00719
    NCGC00016940-01 NCGC00017324-01 NCGC00017324-02
    NCGC00017324-03 NCGC00017324-04 NCGC00017324-05
    NCGC00017324-07 NCGC00017324-08 NCGC00017324-09
    NCGC00254418-01 NSC-633782 NSC-758706
    NSC633782 NSC758706 Nivelipol
    Nor-Vastina Pantok Pharmakon1600-01504236
    Prestwick0_000865 Prestwick1_000865 Prestwick2_000865
    Prestwick3_000865 Prestwick_171 Q670131
    RYMZZMVNJRMUDD-HGQWONQESA- RYMZZMVNJRMUDD-HGQWONQESA-N Rechol
    Rendapid SAM002589969 SBB080618
    SBI-0206773.P001 SC-12666 SCHEMBL2471
    SMR000718785 SPBio_001881 SPBio_002830
    SPECTRUM1504236 SR-05000001894 SR-05000001894-1
    SR-05000001894-2 ST057168 ST2407853
    STK801938 Simcard Simcor
    Simlup Simovil Simvacor
    Simvast CR Simvastatin & Primycin Simvastatin (JP17/USP/INN)
    Simvastatin (Zocor) Simvastatin [USAN:INN:BAN] Simvastatin [USAN:USP:INN:BAN]
    Simvastatin for peak identification, European Pharmacopoeia (EP) Reference Standard Simvastatin lactone Simvastatin(Zocor)
    Simvastatin, 98% Simvastatin, >=97% (HPLC), solid Simvastatin, British Pharmacopoeia (BP) Reference Standard
    Simvastatin, Compactin Simvastatin, European Pharmacopoeia (EP) Reference Standard Simvastatin, Pharmaceutical Secondary Standard
    Simvastatin, United States Pharmacopeia (USP) Reference Standard Simvastatin, analytical standard Simvastatin,(S)
    Simvastatina Simvastatina [Spanish] Simvastatine
    Simvastatine [French] Simvastatinum Simvastatinum [Latin]
    Simvoget Simvotin Sinvacor
    Sinvascor Sivastin SpecPlus_000895
    Spectrum2_001671 Spectrum3_000669 Spectrum4_000632
    Spectrum5_001428 Spectrum_001717 Synvinolin
    TNP00259 Tox21_110696 Tox21_110696_1
    Tox21_300400 UNII-AGG2FN16EV Valemia
    Vasotenal Velostatin W-3044
    Z1741982918 ZINC3780893 Zocor
    Zocor (TN) Zocord Zorced
    Zosta [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxo-tetrahydropyran-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] 2,2-dimethylbutanoate [(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] 2,2-dimethylbutanoate
    butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1 alpha,3 alpha,7 beta,8 beta(2S*,4S*),-8a beta inactive simvastatin s1792
    simvastatin simvastatin predrug

    DrugBank Name Simvastatin
    DrugBank DB00641
    CAS Number 79902-63-9
    PubChem Compound 54454
    KEGG Drug D00434
    PubChem.Substance 46508654
    ChEBI 9150
    PharmGKB PA451363
    ChemSpider 49179
    BindingDB 50139181.0
    TTD DAP001519
    Wikipedia Simvastatin
    DPD 1221

    1. Vuda et al. (2016)
    2. Juge et al. (2016)