Identification

Name
Levamlodipine
Accession Number
DB09237
Type
Small Molecule
Groups
Experimental
Description

Levamlodipine, also known as S-amlodipine, is a pharmacologically active enantiomer of amlodipine, an antihypertensive and anti-anginal medication. Levamlodipine belongs to the dihydropyridine group of calcium channel blockers. This medication is currently marketed in Russia and India [5]. The names S-amlodipine and levamlodipine may be used interchangeably as both substances are the same, however, with differing nomenclature. As a racemic mixture, amlodipine contains (R) and (S)-amlodipine isomers, but only (S)-amlodipine as the active moiety possesses therapeutic activity [4].

Structure
Thumb
Synonyms
  • Levoamlodipine
  • S-amlodipine
International/Other Brands
Asomex (Emcure Pharmaceutical Ltd) / EsCordi Cor (Actavis Pharma) / Eslo (Zuventus Healthcare Ltd.) / Espin (Intas Pharmaceuticals Ltd)
Categories
UNII
0P6NLP6806
CAS number
103129-82-4
Weight
Average: 408.88
Monoisotopic: 408.1451996
Chemical Formula
C20H25ClN2O5
InChI Key
HTIQEAQVCYTUBX-KRWDZBQOSA-N
InChI
InChI=1S/C20H25ClN2O5/c1-4-28-20(25)18-15(11-27-10-9-22)23-12(2)16(19(24)26-3)17(18)13-7-5-6-8-14(13)21/h5-8,17,23H,4,9-11,22H2,1-3H3/t17-/m0/s1
IUPAC Name
3-ethyl 5-methyl (4S)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
SMILES
CCOC(=O)C1=C(COCCN)NC(C)=C([C@@H]1C1=CC=CC=C1Cl)C(=O)OC

Pharmacology

Indication

For the treatment of hypertension and angina [4].

Pharmacodynamics

Levamlodipine decreases blood pressure and reduces cardiovascular oxygen demand, decreasing cardiovascular work. A study was done comparing the effectiveness of amlodipine and levamlodipine, and it was determined that 2.5 mg of S-amlodipine (levamlodipine) administered orally was equally effective as 5mg of amlodipine [4].

Mechanism of action

Levamlodipine blocks the transmembrane influx of calcium into the vascular and cardiac smooth muscles resulting in vasodilation and a subsequent decrease in blood pressure. This drug is an allosteric modulator and acts on the L-type calcium channels. It exerts the same mechanism of action, differing only in its form as an enantiomer [6].

The exact mechanisms by which levamlodipine relieves angina have not been fully understood, but the mechanism is thought to be twofold. Firstly, the modulation of calcium influx caused by levamlodipine leads to decreased peripheral resistance by arteriolar vasodilatation and subsequent reduction in oxygen requirement for cardiac muscle. Secondly, a decrease in coronary vascular resistance which can lead to an increase in coronary blood flow.

Negative inotropic effects can be demonstrated in vitro but such effects have not been observed in live animals at therapeutic doses [6].

Receptor binding studies of amlodipine have shown that out of the two enantiomer forms, only the (S) enantiomer of amlodipine (levamlodipine) binds to and blocks L-type calcium channels. The (R) enantiomer has no activity on these channels [5].

TargetActionsOrganism
UVoltage-dependent L-type calcium channel subunit alpha-1C
antagonist
Humans
UNitric oxide synthase, endothelial
agonist
Humans
UNitric oxide synthase, inducible
agonist
Humans
Absorption

After oral administration of therapeutic doses, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine besylate tablets is not altered by the presence of food [6].

Volume of distribution

The average AUC value (t=48 hrs) of Levamlodipine tablets (2.5 mg) is 95 ± 14 ng hr/ml [8].

Protein binding

93% plasma protein binding in hypertensive patients [5].

Metabolism

Extensively (about 90%) converted to its inactive metabolites by hepatic metabolism. Approximately 10% of the unchanged parent compound and 60% of its metabolites are excreted in the urine [8].

Studies suggest that CYP3A4, rather than CYP3A5, plays a key role in the metabolic clearance of amlodipine in humans [1].

In a metabolic study, or amlodipine enantiomers, S-amlodipine (levamlodipine) was slowly metabolized in human liver microsomes in vitro. Amlodipine dehydrogenation to the pyridine its metabolite, M9; the molecule underwent further underwent oxidative deamination, O-demethylation, and O-dealkylation. These in vitro metabolism data are consistent with amlodipine metabolism and disposition observed in vivo in humans. Data derived from amlodipine metabolism study in expressed P450 in human liver microsomes with P450 inhibitors indicate that CYP3A4 is the primary contributor to amlodipine dehydrogenation, rather than other liver enzymes such as CYP3A5 [3].

Route of elimination

In one study, plasma concentration of (S)-amlodipine was measured after single dose oral administrations to 18 healthy volunteers. The concentration of (S)-enantiomer of amlodipine (Levamlodipine) was significantly higher than that of the inactive (R)-enantiomer (amlodipine). (S)-amlodipine was less rapidly eliminated than its (R) enantiomer [3].

Half life

The plasma elimination half-life of Levamlodipine has been found to be 31 ± 13 hrs [5].

Clearance
Not Available
Toxicity

If overdose should occur, vigilant cardiac and respiratory monitoring should be initiated. As with all calcium channel blockers, the risk of reflex tachycardia Frequent blood pressure measurements is required. Should hypotension occur, supportive measures including elevation of the extremities and administration of fluids should be initiated. Administration of vasopressors (such as phenylephrine) may be considered with attention to monitoring urine output. Intravenous calcium gluconate may reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is unlikely to be beneficial [6].

Affected organisms
  • Humans
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Zhu Y, Wang F, Li Q, Zhu M, Du A, Tang W, Chen W: Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation. Drug Metab Dispos. 2014 Feb;42(2):245-9. doi: 10.1124/dmd.113.055400. Epub 2013 Dec 3. [PubMed:24301608]
  2. Liu Z, Zheng X, Yang X, Wang E, Wang J: Affinity and specificity of levamlodipine-human serum albumin interactions: insights into its carrier function. Biophys J. 2009 May 20;96(10):3917-25. doi: 10.1016/j.bpj.2008.12.3965. [PubMed:19450464]
  3. Laufen H, Leitold M: Enantioselective disposition of oral amlodipine in healthy volunteers. Chirality. 1994;6(7):531-6. doi: 10.1002/chir.530060704. [PubMed:7986667]
  4. Tolerability and effectiveness of (S)-amlodipine compared with racemic amlodipine in hypertension: A systematic review and meta-analysis [Link]
  5. S-Amlodipine [Link]
  6. FDA label Levamlodipine [Link]
  7. Effects of (S)-amlodipine and (R)-amlodipine on L-type calcium channel current of rat ventricular myocytes and cytosolic calcium of aortic smooth muscle cells [Link]
  8. Determination of S-amlodipine in Human Plasma Using Tizanidine as Internal Standard by Lc/Ms/Ms Method [Link]
  9. Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation [Link]
  10. Levamlodipine [Link]
  11. Amlodipine Metabolism in Human Liver Microsomes and Roles of CYP3A4/5 in the Dihydropyridine Dehydrogenation [Link]
  12. The Effects of Amlodipine and (S)-amlodipine on vascular endothelial function in patients with hypertension [Link]
External Links
PubChem Compound
9822750
PubChem Substance
310265141
ChemSpider
7998499
ChEBI
53796
ChEMBL
CHEMBL2111097
HET
6UB
Wikipedia
Levamlodipine
PDB Entries
5kmd

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Male Volunteers2
1CompletedTreatmentHigh Blood Pressure (Hypertension)2
1CompletedTreatmentHigh Blood Pressure (Hypertension) / Hyperlipidemias1
1CompletedTreatmentHyperlipidemias / Hypertension,Essential1
2CompletedTreatmentHigh Blood Pressure (Hypertension)1
3CompletedTreatmentHigh Blood Pressure (Hypertension)2
3Unknown StatusTreatmentHigh Blood Pressure (Hypertension)1
4RecruitingTreatmentHigh Blood Pressure (Hypertension)2
4RecruitingTreatmentHypertension,Essential1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)138https://comptox.epa.gov/dashboard/dsstoxdb/results?formula=1&isotopes=1&search=C24H31ClN2O10
boiling point (°C)413https://comptox.epa.gov/dashboard/dsstoxdb/results?formula=1&isotopes=1&search=C24H31ClN2O10
water solubility81 mg/mLhttp://www.selleckchem.com/products/levamlodipine.html
logP3.30https://comptox.epa.gov/dashboard/dsstoxdb/results?formula=1&isotopes=1&search=C24H31ClN2O10
Predicted Properties
PropertyValueSource
Water Solubility0.0074 mg/mLALOGPS
logP2.22ALOGPS
logP1.64ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)19.12ChemAxon
pKa (Strongest Basic)9.45ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area99.88 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity108.64 m3·mol-1ChemAxon
Polarizability42.11 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as dihydropyridinecarboxylic acids and derivatives. These are compounds containing a dihydropyridine moiety bearing a carboxylic acid group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Hydropyridines
Direct Parent
Dihydropyridinecarboxylic acids and derivatives
Alternative Parents
Chlorobenzenes / Aryl chlorides / Dicarboxylic acids and derivatives / Vinylogous amides / Methyl esters / Enoate esters / Amino acids and derivatives / Azacyclic compounds / Dialkyl ethers / Dialkylamines
show 7 more
Substituents
Dihydropyridinecarboxylic acid derivative / Chlorobenzene / Halobenzene / Aryl chloride / Aryl halide / Monocyclic benzene moiety / Dicarboxylic acid or derivatives / Benzenoid / Vinylogous amide / Alpha,beta-unsaturated carboxylic ester
show 25 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
amlodipine (CHEBI:53796)

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1C
Uniprot ID
Q13936
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1C
Molecular Weight
248974.1 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Tetrahydrobiopterin binding
Specific Function
Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induce...
Gene Name
NOS3
Uniprot ID
P29474
Uniprot Name
Nitric oxide synthase, endothelial
Molecular Weight
133287.62 Da
References
  1. The Effects of Amlodipine and (S)-amlodipine on vascular endothelial function in patients with hypertension [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Tetrahydrobiopterin binding
Specific Function
Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity ...
Gene Name
NOS2
Uniprot ID
P35228
Uniprot Name
Nitric oxide synthase, inducible
Molecular Weight
131116.3 Da
References
  1. The Effects of Amlodipine and (S)-amlodipine on vascular endothelial function in patients with hypertension [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Amlodipine Metabolism in Human Liver Microsomes and Roles of CYP3A4/5 in the Dihydropyridine Dehydrogenation [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Tetrahydrobiopterin binding
Specific Function
Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity ...
Gene Name
NOS2
Uniprot ID
P35228
Uniprot Name
Nitric oxide synthase, inducible
Molecular Weight
131116.3 Da
References
  1. The Effects of Amlodipine and (S)-amlodipine on vascular endothelial function in patients with hypertension [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Tetrahydrobiopterin binding
Specific Function
Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induce...
Gene Name
NOS3
Uniprot ID
P29474
Uniprot Name
Nitric oxide synthase, endothelial
Molecular Weight
133287.62 Da
References
  1. The Effects of Amlodipine and (S)-amlodipine on vascular endothelial function in patients with hypertension [Link]

Drug created on October 23, 2015 10:47 / Updated on November 02, 2018 07:00