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Identification
NameLumefantrine
Accession NumberDB06708
TypeSmall Molecule
GroupsApproved
Description

Lumefantrine is an antimalarial agent used to treat acute uncomplicated malaria. It is administered in combination with artemether for improved efficacy. This combination therapy exerts its effects against the erythrocytic stages of Plasmodium spp. and may be used to treat infections caused by P. falciparum and unidentified Plasmodium species, including infections acquired in chloroquine-resistant areas.

Structure
Thumb
Synonyms
SynonymLanguageCode
(+-)-2,7-Dichloro-9-((Z)-P-chlorobenzylidene)-alpha-((dibutylamino)methyl)fluorene-4-methanolNot AvailableNot Available
2-Dibutylamino-1-[2,7-dichloro-9-(4-chloro-benzylidene)-9H-fluoren-4-yl]-ethanolNot AvailableNot Available
2-Dibutylamino-1-{2,7-dichloro-9-[1-(4-chloro-phenyl)-meth-(Z)-ylidene]-9H-fluoren-4-yl}-ethanolNot AvailableNot Available
BenflumetolNot AvailableNot Available
DL-BenflumelolNot AvailableNot Available
LumefantrineNot AvailableNot Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Coartemtablet20; 120 mg/1; mgoralNovartis Pharmaceuticals Corporation2009-04-07Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixtures
Brand NameIngredients
CoartemArtemether + Lumefantrine
SaltsNot Available
Categories
CAS number82186-77-4
WeightAverage: 528.94
Monoisotopic: 527.154947772
Chemical FormulaC30H32Cl3NO
InChI KeyDYLGFOYVTXJFJP-MYYYXRDXSA-N
InChI
InChI=1S/C30H32Cl3NO/c1-3-5-13-34(14-6-4-2)19-29(35)28-18-23(33)17-27-25(15-20-7-9-21(31)10-8-20)26-16-22(32)11-12-24(26)30(27)28/h7-12,15-18,29,35H,3-6,13-14,19H2,1-2H3/b25-15-
IUPAC Name
2-(dibutylamino)-1-[(9Z)-2,7-dichloro-9-[(4-chlorophenyl)methylidene]-9H-fluoren-4-yl]ethan-1-ol
SMILES
CCCCN(CCCC)CC(O)C1=C2C(=CC(Cl)=C1)\C(=C/C1=CC=C(Cl)C=C1)C1=C2C=CC(Cl)=C1
Taxonomy
ClassificationNot classified
Pharmacology
IndicationLumefantrine and artemether combination therapy is indicated for the treatment of acute uncomplicated malaria caused by Plasmodium falciparum, including malaria acquired in chloroquine-resistant areas. May also be used to treat uncomplicated malaria when the Plasmodium species has not been identified. Indicated for use in adults and children greater than 5 kg.
PharmacodynamicsLumefantrine is a blood schizonticide active against erythrocytic stages of Plasmodium falciparum. It is thought that administration of lumefantrine with artemether results in cooperate antimalarial clearing effects. Artemether has a rapid onset of action and is rapidly cleared from the body. It is thus thought to provide rapid symptomatic relief by reducing the number of malarial parasites. Lumefantrine has a much longer half life and is believed to clear residual parasites.
Mechanism of actionThe exact mechanism by which lumefantrine exerts its antimalarial effect is unknown. However, available data suggest that lumefantrine inhibits the formation of β-hematin by forming a complex with hemin and inhibits nucleic acid and protein synthesis.
AbsorptionFood increases absorption.
Volume of distributionNot Available
Protein binding99.7% bound
Metabolism

Extensively metabolized in the liver primarily by cytochrome P450 3A4. The major metabolite found in plasma is desbutyl-lumefantrine.

SubstrateEnzymesProduct
Lumefantrine
desbutyl-lumefantrineDetails
Route of eliminationNot Available
Half life~ 4.5 days
ClearanceNot Available
ToxicityCommon side effects of combination artemether/lumefantrine therapy in adults include headache, anorexia, dizziness, and asthenia. Common side effects in children include pyrexia, cough, vomiting, anorexia, and headache. Possible serious adverse effects include QT prolongation, bullous eruption, urticaria, splenomegaly (9%), hepatomegaly (adults, 9%; children, 6%), hypersensitivty reaction, and angioedema.
Affected organisms
  • Plasmodium
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9363
Caco-2 permeable+0.6319
P-glycoprotein substrateSubstrate0.8389
P-glycoprotein inhibitor IInhibitor0.6854
P-glycoprotein inhibitor IINon-inhibitor0.5475
Renal organic cation transporterInhibitor0.5792
CYP450 2C9 substrateNon-substrate0.7971
CYP450 2D6 substrateNon-substrate0.9117
CYP450 3A4 substrateSubstrate0.7076
CYP450 1A2 substrateInhibitor0.6872
CYP450 2C9 substrateNon-inhibitor0.7112
CYP450 2D6 substrateInhibitor0.7727
CYP450 2C19 substrateNon-inhibitor0.6525
CYP450 3A4 substrateNon-inhibitor0.6983
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.7168
Ames testNon AMES toxic0.6424
CarcinogenicityNon-carcinogens0.7629
BiodegradationNot ready biodegradable0.9924
Rat acute toxicity2.4077 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.7654
hERG inhibition (predictor II)Inhibitor0.776
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral20; 120 mg/1; mg
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility3.09e-05 mg/mLALOGPS
logP8.34ALOGPS
logP9.19ChemAxon
logS-7.2ALOGPS
pKa (Strongest Acidic)14.1ChemAxon
pKa (Strongest Basic)9.78ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area23.47 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity160.81 m3·mol-1ChemAxon
Polarizability60.69 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Artemether and Lumefantrine (2010). AHFS Drug Information [Electronic versionb]. Retrieved October 24, 2010.
  2. Artemether/Lumefantrine (2010). DrugPoints® System [Electronic version]. Retrieved October 24, 2010.
  3. Novartis. Coartem (artemether/lumefantrine) tablets prescribing information. East Hanover, NJ; 2010 Feb.
External Links
ATC CodesNot Available
AHFS Codes
  • 8:30.08
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AripiprazoleCYP3A4 Inducers may decrease the serum concentration of ARIPiprazole.
ArtemetherAntimalarial Agents may enhance the adverse/toxic effect of Lumefantrine.
BoceprevirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine.
BosentanMay decrease the serum concentration of CYP3A4 Substrates.
CarbamazepineCYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine.
ChloroquineAntimalarial Agents may enhance the adverse/toxic effect of Lumefantrine.
CodeineCYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine.
ConivaptanCYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine.
DabrafenibMay decrease the serum concentration of CYP3A4 Substrates.
DarunavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine.
DeferasiroxMay decrease the serum concentration of CYP3A4 Substrates.
DelavirdineCYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine.
EfavirenzMay decrease the serum concentration of Artemether. Concentrations of dihydroartemisinin (active metabolite of artemether) may also be decreased by efavirenz
EnzalutamideCYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine.
EtravirineMay decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, concentrations of dihydroartemisinin may be decreased. Artemether may increase the serum concentration of Etravirine. Etravirine may increase the serum concentration of Artemether.
FesoterodineCYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine.
FosamprenavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine.
FosphenytoinCYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine.
HalofantrineLumefantrine may enhance the QTc-prolonging effect of Halofantrine.
HydrocodoneCYP3A4 Inducers (Weak) may decrease the serum concentration of Hydrocodone.
HydroxychloroquineAntimalarial Agents may enhance the adverse/toxic effect of Lumefantrine.
IndinavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine.
MefloquineAntimalarial Agents may enhance the adverse/toxic effect of Lumefantrine.
MetoprololCYP2D6 Inhibitors may increase the serum concentration of Metoprolol.
MifepristoneMay enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents.
NebivololCYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol.
NefazodoneCYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine.
NelfinavirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine.
NevirapineMay decrease the serum concentration of Artemether. Nevirapine may also increase or decrease serum concentrations of lumefantrine.
PhenobarbitalCYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine.
PhenytoinCYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine.
PrimaquineAntimalarial Agents may enhance the adverse/toxic effect of Lumefantrine.
PrimidoneCYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine.
ProguanilAntimalarial Agents may enhance the adverse/toxic effect of Lumefantrine.
PyrimethamineAntimalarial Agents may enhance the adverse/toxic effect of Lumefantrine.
QuinineAntimalarial Agents may enhance the adverse/toxic effect of Lumefantrine.
RifampicinCYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine.
RifapentineCYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine.
SaxagliptinCYP3A4 Inducers may decrease the serum concentration of Saxagliptin.
SiltuximabMay decrease the serum concentration of CYP3A4 Substrates.
TamoxifenCYP2D6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites.
TelaprevirCYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine.
ThioridazineCYP2D6 Inhibitors may increase the serum concentration of Thioridazine.
TocilizumabMay decrease the serum concentration of CYP3A4 Substrates.
TramadolCYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects.
Food Interactions
  • Grapefruit juice may increase the toxicity of artemether and lumefantrine by inhibiting their metabolism.
  • Take with food as food increases the absorption of lumefantrine and artemether.

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Novartis. Coartem (artemether/lumefantrine) tablets prescribing information. East Hanover, NJ; 2010 Feb.

2. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Novartis. Coartem (artemether/lumefantrine) tablets prescribing information. East Hanover, NJ; 2010 Feb.

Comments
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Drug created on May 15, 2010 19:04 / Updated on September 16, 2013 18:04