Lovastatin was the first statin drug approved for treatment of high cholesterol. It was isolated from fermentation of Aspergillus terreus in 1978 and marketed in 1987. Lovastatin is a class I statin with a polar head group and hydrophobic moiety. It works by competitively inhibiting HMG-CoA reductase, the rate limiting enzyme in cholesterol biosynthesis. Lovastatin is administered orally and converted to its active form in the liver. It has a biological half-life of 13.37 hours and is metabolized and eliminated primarily in the feces. Adverse effects include myopathy and rhabdomyolysis.

1. Ajit Kumar Yadav
Msc Biomedical science
Delhi University
LOVASTATIN

2. LOVASTATIN
Introduction
• In 1978, Merck isolated a closely related structure (to
Mevastatin a potent Inhibitor of HMGR) called mevinolin
from the fermentation broth of Aspergillus terreus .
• The drug was marketed in 1987 as lovastatin and it
revolutionized the treatment of hypercholesterolaemia
(high cholesterol levels).
• Statins are classified into Class I and Class II Statin based
on their Hydrophobic moiety. Lovastatin is a class I statin.
• It is a naturally occurring compound found in low
concentrations in food such as oyster mushrooms, red
yeast rice, etc.
Polar head group
Lactone ring
Hydrophobic
Moiety
Fig.- Lovastatin
Decalin ring

3. LOVASTATIN
Patent
• Lovastatin was first approved for sale by Merck Frosst Canada
Ltd. Under the brand name MEVACOR and is used for the
treatment of elevated blood cholesterol.
• The application for the 380 patent was filed in Canada on June
11, 1980 and issued on January 31,1984 to Merck & Co.

4. Property Name Property Value
Molecular Weight 404.5 g/ mol
LogP 4.3
Hydrogen Bond Donor Count 1
Hydrogen Bond Acceptor Count 5
Rotatable Bond Count 7
Topological Polar Surface Area 72.8 Ų
Heavy Atom Count 29
Formal Charge 0
Defined Atom Stereocenter Count 8
Chemical and Physical Properties
LOVASTATIN
Polar head group
Lactone ring
Hydrophobic
Moiety
Fig.- Lovastatin
Decalin ring

5. Physical Properties
• White Crystalline solid
• Melting Point = 174.5°C
• Boiling Point = 559.2°C at 760 mmHg
• Solubiliity -
- Insoluble in water
- Very soluble in Chloroform, soluble in dimethyl formamide,
slightly soluble in acetone and ethanol.
• Uv Spectra - UV max at 231, 238, 247 nm
LOVASTATIN

6. LOVASTATIN
Drug indicated for Diseases
Lovastatin is a commonly used as cholesterol lowering agent
• Hypercholesterolemia (High cholesterol level)
• Dyslipidaemia ( an abnormal amount of lipids i.e. average to moderately elevated
total-C and LDL-C, and below average HDL-C.)
• Lovastatin also indicated to reduce the risk of myocardial infarction, unstable angina
and clinical atherosclerosis.
• Besides a cholesterol lowering agent, there is growing evidence that statins have
immunomodulatory activities.

7. LOVASTATIN
Mechanism of action for Lovastatin —
Pharmacodynamics
• The rate limiting step in biosynthesis of cholesterol pathway is the reduction
of b- hydroxy -b- methylglutaryl -coenzyme A (HMG-CoA) to mevalonate by
HMG-CoA reductase.

8. LOVASTATIN
• The statins work by acting as competitive inhibitors. They mimic the natural
substrate(HMG-SCoA) and compete with it in order to bind to the active site
of HMG-SCoA Reductase.
• The statins contain an extra hydrophobic region which can form
additional hydrophobic interactions with a hydrophobic binding
region present in the enzyme. This allows the statins to bind
more strongly.
Fig. – Structural Comparison of HMG-SCoA with Statins
HMG- SCoA Statin
There is one other interesting feature
about the statins. They are actually
more similar to the first intermediate
mevaldyl CoA than to the substrate.
Assuming that mevaldyl CoA is less
stable than the substrate, this implies
that the statins bear some
resemblance to the transition state
leading to mevaldyl CoA.
Consequently, they would be
expected to have a stronger binding
interaction than the natural substrate
and are likely to be acting as
transitionstate Analogues.

9. LOVASTATIN
• The polar head-group of the statins
binds in a similar fashion as the
substrate.
• There is also no other hydrophobic
region into which the statins could
Bind.
• Thus, the statins are effective
inhibitors because they can take
advantage of the enzyme’s flexibility
and essentially create their own
binding site.

10. LOVASTATIN
Volume of Distribution
• Lovastatin is able to cross the blood-brain barrier and placenta.
Biological Half Life
• Lovastatin half-life is reported to be of 13.37 hours.
• The elimination half-life of the hydroxy acid form of lovastatin is reported to be of 0.7-3 hours
Pharmacokinetics
Absorption
• Lovastatin Cmax was found to be 3.013ng/mL with a Tmax of 3.36 hours.
• Plasma concentrations of total radioactivity peaked at 2 hours and declined rapidly to about 10%
of peak by 24 hours post dose.
• Absorption of lovastatin, estimated relative to an intravenous reference dose averaged about
30% of an oral dose.

11. LOVASTATIN
• Lovastatins are lactone Prodrugs.
• They are administered orally and pass unchanged into the liver where the lactone ring is
hydrolyzed to the active hydroxy- heptanoic acid form of the drug.
• metabolized by the microsomal hepatic enzyme system (Cytochrome P-450).
Metabolism

12. LOVASTATIN
• Following an oral dose of 14C-labeled lovastatin to man, 10% of the dose
was excreted in urine and 83% in feces.
• The latter represents absorbed drug excreted in bile, together with
unabsorbed drug.
Route of Elimination
• The major active metabolites present in human plasma are the beta- hydroxy acid of lovastatin,
its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives.

13. LOVASTATIN
• Myopathy (as muscle pain, tenderness or weakness
with high creatine kinase level in blood.)
• Rhabdomyolysis with or without acute renal failure
• Hepatic failure
• Testicular atrophy
• The median lethal dose of lovastatin is higher than 15 g/m2.
Toxicity
• Lovastatin, like other inhibitors of HMG-CoA reductase,
causes :--

14. LOVASTATIN
 An Introduction to Medicinal Chemistry by Graham L. Patrick
 Medicinal Chemistry - Gareth Thomas
 https://pubchem.ncbi.nlm.nih.gov/compound/Lovastatin
 www.go.drugbank.com
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