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Identification
NameArtemether
Accession NumberDB06697
TypeSmall Molecule
GroupsApproved
Description

Artemether is an antimalarial agent used to treat acute uncomplicated malaria. It is administered in combination with lumefantrine 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
(1R,4S,5R,8S,9R,10S,12R,13R)-10-Methoxy-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0^{4,13}.0^{8,13}]hexadecaneNot AvailableNot Available
10-Methoxy-1,5,9-trimethyl-(1R,4S,5R,8S,9R,10S,12R,13R)-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecaneNot AvailableNot Available
ArtemeteroNot AvailableNot Available
ArtemetherumNot AvailableNot Available
Artemisininelactol methyl etherNot AvailableNot Available
beta-ArtemetherNot AvailableNot Available
beta-Dihydroartemisinin methyl etherNot AvailableNot Available
Dihydroartemisinin methyl etherNot AvailableNot Available
Dihydroqinghaosu methyl etherNot AvailableNot Available
Methyl-dihydroartemisinineNot AvailableNot Available
SM-224Not AvailableNot Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixtures
Brand NameIngredients
Coartemartemether + lumefantrine
Riametartemether + lumefantrine
SaltsNot Available
Categories
CAS number71963-77-4
WeightAverage: 298.3746
Monoisotopic: 298.178023942
Chemical FormulaC16H26O5
InChI KeySXYIRMFQILZOAM-HVNFFKDJSA-N
InChI
InChI=1S/C16H26O5/c1-9-5-6-12-10(2)13(17-4)18-14-16(12)11(9)7-8-15(3,19-14)20-21-16/h9-14H,5-8H2,1-4H3/t9-,10-,11+,12+,13+,14-,15-,16-/m1/s1
IUPAC Name
(1R,4S,5R,8S,9R,10S,12R,13R)-10-methoxy-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0⁴,¹³.0⁸,¹³]hexadecane
SMILES
[H][C@@]12CC[C@@H](C)[C@]3([H])CC[C@@]4(C)OO[C@@]13[C@]([H])(O[C@H](OC)[C@@H]2C)O4
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as artemisinins. These are sesquiterpenoids originally isolated from the herb Artemisia annua. Their structure is based on artemisinin, a tetracyclic compound that contains a 1,2-dioxepane fused to an octahydrobenzopyran moiety. The internal peroxide bridge is believed to be a key to the mode of action of artemisinins.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassPrenol lipids
Sub ClassSesquiterpenoids
Direct ParentArtemisinins
Alternative Parents
Substituents
  • Artemisinin skeleton
  • Oxepane
  • 1,2,4-trioxane
  • Oxane
  • Dialkyl peroxide
  • Oxacycle
  • Organoheterocyclic compound
  • Acetal
  • Hydrocarbon derivative
  • Organooxygen compound
  • Aliphatic heteropolycyclic compound
Molecular FrameworkAliphatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationArtemether and lumefantrine 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.
PharmacodynamicsIn the body, artemether is metabolized into the active metabolite metabolite dihydroartemisinin. The drug works against the erythrocytic stages of P. falciparum by inhibiting nucleic acid and protein synthesis. Artemether is administered in combination with lumefantrine for improved efficacy. Artemether has a rapid onset of action and is rapidly cleared from the body. It is thought that artemether provides 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 actionInvolves an interaction with ferriprotoporphyrin IX (“heme”), or ferrous ions, in the acidic parasite food vacuole, which results in the generation of cytotoxic radical species. The generally accepted mechanism of action of peroxide antimalarials involves interaction of the peroxide-containing drug with heme, a hemoglobin degradation byproduct, derived from proteolysis of hemoglobin. This interaction is believed to result in the formation of a range of potentially toxic oxygen and carbon-centered radicals.
AbsorptionFood increases absorption.
Volume of distributionNot Available
Protein bindingArtemether and lumefantrine are both highly bound to human serum proteins in vitro (95.4% and 99.7%, respectively). Dihydroartemisinin is also bound to human serum proteins (47% to 76%).
Metabolism

Rapidly metablized to its active metabolite, dihydroartemisinin.

SubstrateEnzymesProduct
Artemether
Dihydroartemisinin (DHA)Details
Artemether
Not Available
9,10-dihydrodeoxy-artemsininDetails
Artemether
Not Available
Alpha-dihydroartemisininDetails
Artemether
Not Available
DeoxyartemsininDetails
Artemether
Not Available
Deoxydihydro-artemisininDetails
Route of eliminationNot Available
Half lifeArtemether, 1.6 +/- 0.7 and 2.2 +/- 1.9 hr; Dihydroartemisinin, 1.6 +/- 0.6 and 2.2 +/- 1.5 hr
ClearanceNot Available
ToxicityAnimal studies on acute toxicity show that the LD50 of Artemether in mice is a single i.g. administration of 895mg/kg and a single i.m. injection of 296mg/kg dose; in rats, the LD50 is a single i.m. injection of 597mg/kg dose.
Affected organisms
  • Plasmodium
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9012
Blood Brain Barrier+0.9393
Caco-2 permeable+0.7876
P-glycoprotein substrateSubstrate0.6031
P-glycoprotein inhibitor IInhibitor0.8918
P-glycoprotein inhibitor IINon-inhibitor0.7056
Renal organic cation transporterNon-inhibitor0.8178
CYP450 2C9 substrateNon-substrate0.8665
CYP450 2D6 substrateSubstrate0.5341
CYP450 3A4 substrateSubstrate0.7023
CYP450 1A2 substrateInhibitor0.6829
CYP450 2C9 substrateNon-inhibitor0.9413
CYP450 2D6 substrateNon-inhibitor0.9474
CYP450 2C19 substrateNon-inhibitor0.8733
CYP450 3A4 substrateNon-inhibitor0.9434
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9672
Ames testNon AMES toxic0.7285
CarcinogenicityNon-carcinogens0.9179
BiodegradationNot ready biodegradable0.9956
Rat acute toxicity2.2114 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9502
hERG inhibition (predictor II)Non-inhibitor0.7601
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point86-90Not Available
water solubilityInsoluble # http://www.rxlist.com/coartem-drug.htm
logP3.53AVERY,MA ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.457 mg/mLALOGPS
logP3.02ALOGPS
logP3.48ChemAxon
logS-2.8ALOGPS
pKa (Strongest Basic)-3.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area46.15 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity74.66 m3·mol-1ChemAxon
Polarizability32.12 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (7.86 KB)
SpectraNot Available
References
Synthesis Reference
  1. Haynes RK, Vonwiller SC: Extraction of artemisinin and artemisinic acid: preparation of artemether and new analogues. Trans R Soc Trop Med Hyg. 1994 Jun;88 Suppl 1:S23-6. Pubmed
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.
  4. Makanga M, Krudsood S: The clinical efficacy of artemether/lumefantrine (Coartem). Malar J. 2009 Oct 12;8 Suppl 1:S5. doi: 10.1186/1475-2875-8-S1-S5. Pubmed
  5. Mutabingwa TK, Adam I: Use of artemether-lumefantrine to treat malaria during pregnancy: what do we know and need to know? Expert Rev Anti Infect Ther. 2013 Feb;11(2):125-35. doi: 10.1586/eri.12.169. Pubmed
  6. Haynes RK, Vonwiller SC: Extraction of artemisinin and artemisinic acid: preparation of artemether and new analogues. Trans R Soc Trop Med Hyg. 1994 Jun;88 Suppl 1:S23-6. Pubmed
External Links
ATC CodesP01BE02
AHFS Codes
  • 8:30.08
PDB EntriesNot Available
FDA labelDownload (1.73 MB)
MSDSDownload (566 KB)
Interactions
Drug Interactions
Drug
AripiprazoleCYP3A4 Inducers may decrease the serum concentration of ARIPiprazole.
BosentanMay decrease the serum concentration of CYP3A4 Substrates.
CarbamazepineCYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether.
ChloroquineMay enhance the adverse/toxic effect of Antimalarial Agents.
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.
DabrafenibMay decrease the serum concentration of CYP3A4 Substrates.
DeferasiroxMay decrease the serum concentration of CYP3A4 Substrates.
DesogestrelMay decrease the serum concentration of Contraceptives (Estrogens).
DrospirenoneMay decrease the serum concentration of Contraceptives (Progestins).
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 serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether.
Ethinyl EstradiolMay decrease the serum concentration of Contraceptives (Estrogens).
EthynodiolMay decrease the serum concentration of Contraceptives (Estrogens).
EtonogestrelMay decrease the serum concentration of Contraceptives (Progestins).
EtravirineEtravirine may 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.
FosphenytoinCYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether.
HalofantrineLumefantrine may enhance the QTc-prolonging effect of Halofantrine.
HydrocodoneCYP3A4 Inducers (Weak) may decrease the serum concentration of Hydrocodone.
HydroxychloroquineMay enhance the adverse/toxic effect of Antimalarial Agents.
LevonorgestrelMay decrease the serum concentration of Contraceptives (Progestins).
LumefantrineAntimalarial Agents may enhance the adverse/toxic effect of Lumefantrine.
Medroxyprogesterone AcetateMay decrease the serum concentration of Contraceptives (Progestins).
MefloquineMay enhance the adverse/toxic effect of Antimalarial Agents.
MestranolMay decrease the serum concentration of Contraceptives (Estrogens).
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.
NevirapineNevirapine may decrease the serum concentration of Artemether. Nevirapine may also increase or decrease serum concentrations of lumefantrine.
NorelgestrominMay decrease the serum concentration of Contraceptives (Estrogens).
NorethindroneMay decrease the serum concentration of Contraceptives (Progestins).
NorgestimateMay decrease the serum concentration of Contraceptives (Progestins).
PhenobarbitalCYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether.
PhenytoinCYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether.
PrimaquineMay enhance the adverse/toxic effect of Antimalarial Agents.
PrimidoneCYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether.
ProguanilMay enhance the adverse/toxic effect of Antimalarial Agents.
PyrimethamineMay enhance the adverse/toxic effect of Antimalarial Agents.
QuinineMay enhance the adverse/toxic effect of Antimalarial Agents.
RifampicinCYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether.
RifapentineCYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether.
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.
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 artemether and lumefantrine.

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

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. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

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

3. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. Novartis. Coartem (artemether/lumefantrine) tablets prescribing information. East Hanover, NJ; 2010 Feb.
  2. Elsherbiny DA, Asimus SA, Karlsson MO, Ashton M, Simonsson US: A model based assessment of the CYP2B6 and CYP2C19 inductive properties by artemisinin antimalarials: implications for combination regimens. J Pharmacokinet Pharmacodyn. 2008 Apr;35(2):203-17. Epub 2008 Mar 19. Pubmed

4. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

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

5. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Novartis. Coartem (artemether/lumefantrine) tablets prescribing information. East Hanover, NJ; 2010 Feb.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  3. Elsherbiny DA, Asimus SA, Karlsson MO, Ashton M, Simonsson US: A model based assessment of the CYP2B6 and CYP2C19 inductive properties by artemisinin antimalarials: implications for combination regimens. J Pharmacokinet Pharmacodyn. 2008 Apr;35(2):203-17. Epub 2008 Mar 19. Pubmed

6. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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Drug created on May 05, 2010 12:03 / Updated on September 16, 2013 18:04