General
Preferred name
lovastatin
Synonyms
Mevinolin ()
MK-803 ()
Lovastatin (Mevacor) ()
Lovastatin75330-75-5 ()
Lovastatin (MK-803) ()
Mevinolin,Mevacor ()
Lovastatin-d9 ()
Mevacor ()
NSC-758662 ()
Mevlor ()
Mevinacor ()
Mevinacor 40 ()
Altoprev ()
Mevinacor 10 ()
C10AA02 ()
Sivlor ()
6.alpha.-methylcompactin ()
Monacolin k ()
L-154803 ()
Simvastatin impurity, lovastatin- ()
6.ALPHA.-METHYLCOMPACTIN ()
ALTOPREV ()
MEVINACOR ()
MEVINACOR 10 ()
MEVINACOR 40 ()
MEVLOR ()
MONACOLIN K ()
SIMVASTATIN IMPURITY, LOVASTATIN- ()
SIVLOR ()
P&D ID
PD003114
CAS
75330-75-5
71949-96-7
Tags
natural product
drug
probe
prodrug
available
Approved by
FDA
First approval
1987
Drug indication
Inhibitor (HMG-CoA reductase)
Antihyperlipidemic
Hypercholesterolaemia
Cardiovascular disease
Drug Status
investigational
approved
Max Phase
4.0
Probe info
Probe selectivity
protein-selective
Probe type
P&D approved
calculated probe
Probe sources
Probe targets
[[ compound.targets[t].gene_name ]]
Probe control
Orthogonal probes
3
No orthogonal probes found
Similar probes
2
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
DESCRIPTION
NB: there may be ambiguity in the chiral specification in the reported literature
ROE
Lovastatin excretion is reported to be represented of about 10% of urine elimination and 83% of fecal elimination. The elimination through the bile is represented either by the absorbed and unabsorbed drug.[L5284]
MOA
Lovastatin is a potent competitive inhibitor of HMG-CoA reductase and it presents a Ki of 1.4 nM. The inhibition of this enzyme directly interferes with the biosynthesis of mevalonic acid which is the precursor in the production pathway of terpenes and steroids.[A174553] The effect of lovastatin is expected to be mainly directed to the liver since it is the major site of cholesterol biosynthesis, lipoprotein production and LDL catabolism, however, the synthesis of cholesterol is also necessary for extrahepatic tissues. Hence, long term treatment with lovastatin can derive in the onset of adverse reactions due to the extrahepatic action.[A174580] Some reports have indicated a role of lovastatin in the inhibition of DNA synthesis and cell proliferation. This activity seems to be related to the effect that lovastatin presents against adenyl cyclase alpha subunits as observed by a lovastatin-induced decrease on ADP-ribosylation.[A174568]
TOXICITY
The median lethal dose of lovastatin is higher than 15 g/m2. The administration of very high dosages of lovastatin does not seem to provide with significant adverse symptoms. The maximal dose taken is of 5-6 g.[FDA label] In carcinogenic studies, there is an increase in the incidence of hepatocellular carcinomas and adenomas, pulmonary adenomas, papilloma in non-glandular mucose in stomach and thyroid neoplasms. On the fertility side, lovastatin has been reported to present testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation which derived into decreased fertility in males. Lastly, there is no evidence of mutagenicity induced by lovastatin.[FDA label]
METABOLISM
Lovastatin is given as a lactone prodrug and thus, in order to produce its mechanism of action, it is required to be converted to the active beta-hydroxy form. This drug activation process does not seem to be related to CYP isoenzyme activity[A414] but rather to be controlled by the activity of serum paraoxonase.[A15320] Afterward, the metabolism of lovastatin is mainly performed by cytochrome CYP3A4 and to a lesser extent by CYP2D6.[L5293] The uptake of lovastatin by the liver is enhanced by the activity of OATP1B1.[A35026] The metabolism of lovastatin produces several polar metabolites from which one fraction consists of a 2:1 mixture of 6-hydroxy-lovastatin and delta 4,5-3-hydroxy lovastatin. Additionally, it is possible to find desacyl-delta 4a,6,8-dehydro lovastatin which is a single aromatized product and 4, 8a, 1-3-hydroxy lovastatin.[A174589]
ABSORPTION
Studies suggest that less than 5% of the oral dose reaches the general circulation as active inhibitors and the time to peak serum concentration is 2-4 hours. Lovastatin undergoes extensive first-pass metabolism so the availability of the drug in the system is low and variable.[L5284] The peak concentrations of lovastatin when a dose of 10-40 mg is administered are reported to range from 1.04-4.03 ng/ml and an AUC of 14-53 ng.h/ml. This indicates that lovastatin presents a dose-dependent pharmacokinetic profile.[A174586]
HALF-LIFE
Lovastatin half-life is reported to be of 4.5 hours.[L5284] The elimination half-life of the hydroxy acid form of lovastatin is reported to be of 0.7-3 hours.[A174583]
MOA
Lovastatin is a potent competitive inhibitor of HMG-CoA reductase and it presents a Ki of 1.4 nM. The inhibition of this enzyme directly interferes with the biosynthesis of mevalonic acid which is the precursor in the production pathway of terpenes and steroids.[A174553]; ; The effect of lovastatin is expected to be mainly directed to the liver since it is the major site of cholesterol biosynthesis, lipoprotein production and LDL catabolism, however, the synthesis of cholesterol is also necessary for extrahepatic tissues. Hence, long term treatment with lovastatin can derive in the onset of adverse reactions due to the extrahepatic action.[A174580]; ; Some reports have indicated a role of lovastatin in the inhibition of DNA synthesis and cell proliferation. This activity seems to be related to the effect that lovastatin presents against adenyl cyclase alpha subunits as observed by a lovastatin-induced decrease on ADP-ribosylation.[A174568]
TOXICITY
The median lethal dose of lovastatin is higher than 15 g/m2. The administration of very high dosages of lovastatin does not seem to provide with significant adverse symptoms. The maximal dose taken is of 5-6 g.[FDA label]; ; In carcinogenic studies, there is an increase in the incidence of hepatocellular carcinomas and adenomas, pulmonary adenomas, papilloma in non-glandular mucose in stomach and thyroid neoplasms. On the fertility side, lovastatin has been reported to present testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation which derived into decreased fertility in males. Lastly, there is no evidence of mutagenicity induced by lovastatin.[FDA label]
METABOLISM
Lovastatin is given as a lactone prodrug and thus, in order to produce its mechanism of action, it is required to be converted to the active beta-hydroxy form. This drug activation process does not seem to be related to CYP isoenzyme activity[A414] but rather to be controlled by the activity of serum paraoxonase.[A15320]; ; Afterward, the metabolism of lovastatin is mainly performed by cytochrome CYP3A4 and to a lesser extent by CYP2D6.[L5293] The uptake of lovastatin by the liver is enhanced by the activity of OATP1B1.[A35026] The metabolism of lovastatin produces several polar metabolites from which one fraction consists of a 2:1 mixture of 6-hydroxy-lovastatin and delta 4,5-3-hydroxy lovastatin. Additionally, it is possible to find desacyl-delta 4a,6,8-dehydro lovastatin which is a single aromatized product and 4, 8a, 1-3-hydroxy lovastatin.[A174589]
ABSORPTION
Studies suggest that less than 5% of the oral dose reaches the general circulation as active inhibitors and the time to peak serum concentration is 2-4 hours. Lovastatin undergoes extensive first-pass metabolism so the availability of the drug in the system is low and variable.[L5284]; ; The peak concentrations of lovastatin when a dose of 10-40 mg is administered are reported to range from 1.04-4.03 ng/ml and an AUC of 14-53 ng.h/ml. This indicates that lovastatin presents a dose-dependent pharmacokinetic profile.[A174586]
DESCRIPTION
Lovastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA) inhibitor; a statin drug used for the prevention of cardiovascular diseases.
NB: there may be ambiguity in the chiral specification in the reported literature, compared to the structure represented here. (GtoPdb)
NB: there may be ambiguity in the chiral specification in the reported literature, compared to the structure represented here. (GtoPdb)
PHARMACODYNAMICS
Based on the mechanism of action of lovastatin, we can understand that the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase produces a limitation in cholesterol biosynthesis and this limitation induces an increase in the generation of microsomal HMG-CoA reductase and cell surface LDL receptors. Hence, cell cholesterol is provided by de novo synthesis and by receptor-cell uptake of LDL from the blood which resets tissue homeostasis.[A174583] The administration of lovastatin is observed by the significant inhibition of cholesterol synthesis. The 50% inhibitory dose is known to be of 46 mcg/kg which is translated into a reduction of approximately 30% of plasma cholesterol.[A174553] This effect is obtained by the reduction of low-density lipoprotein C, reduction of circulating LDL particles, modest reductions on very low-density lipoprotein C and plasma triglycerides as well as an increase in high-density lipoprotein C.[L5284] The effect of lovastatin against LDL cholesterol is thought to be related to the normal mechanism of action as well as to an increase in LDL receptor family activity.[A174580] In hypercholesterolemia animal models and clinical trials, lovastatin has been proven to effectively reduce the total and LDL cholesterol in serum.[A174565] In these clinical reports, lovastatin was shown to reduce by 25-40% the concentration of LDL cholesterol and total cholesterol in plasma in patients suffering from hypercholesterolemia.[A174580]
INDICATION
Lovastatin is indicated as an intervention alternative in individuals presenting dyslipidemia at risk of atherosclerotic vascular disease. The administration of this agent should be accompanied by the implementation of a fat and cholesterol-restricted diet.[FDA label] In individuals with risk factors related to elevated total cholesterol, elevated LDL cholesterol and below average HDL cholesterol, lovastatin can be used to reduce the risk of myocardial infarction, unstable angina and coronary revascularization procedures.[FDA label] As well, lovastatin is indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease.[FDA label] Lovastatin is used as part of the multiple risk factor intervention with a saturated fat-restricted diet in patients with significantly increased risk of atherosclerotic vascular disease due to hypercholesterolemia. The administration of lovastatin is restricted to patients to whom the administration of a diet restricted in saturated fat and cholesterol or the application of nonpharmaceutical measures are inadequate or irresponsive.[FDA label] Lovastatin is indicated as an adjunct therapy to diet to reduce total cholesterol, LDL cholesterol and apolipoprotein B level in adolescents between 10-17 years. The administration of lovastatin is restricted to patients in which adequate diet has been unresponsive as seen by LDL cholesterol higher than 189 mg/dL or LDL cholesterol higher than 160 mg/dL and history of family cardiovascular disease or with two or more cardiovascular disease risk factors.[FDA label] Before administering lovastatin, it is important to rule out the presence of secondary causes of hypercholesterolemia and a lipid profile should be performed.[FDA label] Lovastatin is used off-label for the treatment and management of peripheral artery disease.[T415]
PHARMACODYNAMICS
Based on the mechanism of action of lovastatin, we can understand that the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase produces a limitation in cholesterol biosynthesis and this limitation induces an increase in the generation of microsomal HMG-CoA reductase and cell surface LDL receptors. Hence, cell cholesterol is provided by de novo synthesis and by receptor-cell uptake of LDL from the blood which resets tissue homeostasis.[A174583]; ; The administration of lovastatin is observed by the significant inhibition of cholesterol synthesis. The 50% inhibitory dose is known to be of 46 mcg/kg which is translated into a reduction of approximately 30% of plasma cholesterol.[A174553] This effect is obtained by the reduction of low-density lipoprotein C, reduction of circulating LDL particles, modest reductions on very low-density lipoprotein C and plasma triglycerides as well as an increase in high-density lipoprotein C.[L5284] The effect of lovastatin against LDL cholesterol is thought to be related to the normal mechanism of action as well as to an increase in LDL receptor family activity.[A174580]; ; In hypercholesterolemia animal models and clinical trials, lovastatin has been proven to effectively reduce the total and LDL cholesterol in serum.[A174565] In these clinical reports, lovastatin was shown to reduce by 25-40% the concentration of LDL cholesterol and total cholesterol in plasma in patients suffering from hypercholesterolemia.[A174580]
INDICATION
Lovastatin is indicated as an intervention alternative in individuals presenting dyslipidemia at risk of atherosclerotic vascular disease. The administration of this agent should be accompanied by the implementation of a fat and cholesterol-restricted diet.[FDA label]; ; In individuals with risk factors related to elevated total cholesterol, elevated LDL cholesterol and below average HDL cholesterol, lovastatin can be used to reduce the risk of myocardial infarction, unstable angina and coronary revascularization procedures.[FDA label]; ; As well, lovastatin is indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease.[FDA label]; ; Lovastatin is used as part of the multiple risk factor intervention with a saturated fat-restricted diet in patients with significantly increased risk of atherosclerotic vascular disease due to hypercholesterolemia. The administration of lovastatin is restricted to patients to whom the administration of a diet restricted in saturated fat and cholesterol or the application of nonpharmaceutical measures are inadequate or irresponsive.[FDA label] ; ; Lovastatin is indicated as an adjunct therapy to diet to reduce total cholesterol, LDL cholesterol and apolipoprotein B level in adolescents between 10-17 years. The administration of lovastatin is restricted to patients in which adequate diet has been unresponsive as seen by LDL cholesterol higher than 189 mg/dL or LDL cholesterol higher than 160 mg/dL and history of family cardiovascular disease or with two or more cardiovascular disease risk factors.[FDA label]; ; Before administering lovastatin, it is important to rule out the presence of secondary causes of hypercholesterolemia and a lipid profile should be performed.[FDA label]; ; Lovastatin is used off-label for the treatment and management of peripheral artery disease.[T415]
DESCRIPTION
Protein phosphatase 1 and 2A inhibitor
(Tocris Bioactive Compound Library)
DESCRIPTION
Potent HMG-CoA reductase inhibitor
(Tocriscreen Plus)
DESCRIPTION
HMG-CoA reductase inhibitor
(Tocriscreen Total)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
8
Organisms
3
Compound Sets
36
AdooQ Bioactive Compound Library
ChEMBL Approved Drugs
ChEMBL Drugs
Concise Guide to Pharmacology 2017/18
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DrugBank Approved Drugs
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DrugCentral Approved Drugs
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DrugMAP Approved Drugs
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High-quality chemical probes
LSP-MoA library (Laboratory of Systems Pharmacology)
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NIH Clinical Collections (NCC)
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NURSA ligand set
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ReFrame library
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ZINC Tool Compounds
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
50
Molecular Weight
404.26
Hydrogen Bond Acceptors
5
Hydrogen Bond Donors
1
Rotatable Bonds
6
Ring Count
3
Aromatic Ring Count
0
cLogP
4.2
TPSA
72.83
Fraction CSP3
0.75
Chiral centers
8.0
Largest ring
6.0
QED
0.67
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Target Type
Enzymes
Pathway
Metabolism
Apoptosis
Autophagy
Metabolic Enzyme/Protease
Target
HMG-CoA Reductase
HDAC2, HMGCR, ITGAL, NR1I2
Ferroptosis
HMG-CoA Reductase (HMGCR)
Autophagy,HMG-CoA Reductase
MOA
HMG-CoA Reductase inhibitor
Inhibitor
HMGCR inhibitor
Disease Area
cardiology, endocrinology
Indication
coronary heart disease, myocardial infarction, hypercholesterolemia
Therapeutic Class
Anticholesteremic Agents
Recommended Cell Concentration
None
Source data
