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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
(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}]hexadecane
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]hexadecane
Artemetero
Artemetherum
Artemisininelactol methyl ether
beta-Artemether
beta-Dihydroartemisinin methyl ether
Dihydroartemisinin methyl ether
Dihydroqinghaosu methyl ether
Methyl-dihydroartemisinine
SM-224
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixtures
NameLabellerIngredients
CoartemNovartis Pharmaceuticals Corporation
SaltsNot Available
Categories
UNIIC7D6T3H22J
CAS number71963-77-4
WeightAverage: 298.3746
Monoisotopic: 298.178023942
Chemical FormulaC16H26O5
InChI KeyInChIKey=SXYIRMFQILZOAM-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[[email protected]](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.
Related Articles
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
Pathways
PathwayCategorySMPDB ID
Artemether Metabolism PathwayDrug metabolismSMP00651
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 inhibitorNon-inhibitor0.9413
CYP450 2D6 inhibitorNon-inhibitor0.9474
CYP450 2C19 inhibitorNon-inhibitor0.8733
CYP450 3A4 inhibitorNon-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
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral
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 References
  1. 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:19818172 ]
  2. 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:23409819 ]
  3. 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:8053018 ]
External Links
ATC CodesP01BE02P01BF01
AHFS Codes
  • 8:30.08
PDB EntriesNot Available
FDA labelDownload (1.73 MB)
MSDSDownload (566 KB)
Interactions
Drug Interactions
Drug
AcepromazineThe serum concentration of Acepromazine can be increased when it is combined with Artemether.
ArtesunateThe risk or severity of adverse effects can be increased when Artemether is combined with Artesunate.
BexaroteneThe serum concentration of Artemether can be decreased when it is combined with Bexarotene.
CarbamazepineThe serum concentration of the active metabolites of Artemether can be reduced when Artemether is used in combination with Carbamazepine resulting in a loss in efficacy.
ChloroquineThe risk or severity of adverse effects can be increased when Artemether is combined with Chloroquine.
ChlorotrianiseneThe serum concentration of Chlorotrianisene can be decreased when it is combined with Artemether.
CitalopramCitalopram may increase the QTc-prolonging activities of Artemether.
DapsoneThe risk or severity of adverse effects can be increased when Artemether is combined with Dapsone.
DienogestThe serum concentration of Dienogest can be decreased when it is combined with Artemether.
DofetilideDofetilide may increase the QTc-prolonging activities of Artemether.
DoxorubicinThe serum concentration of Doxorubicin can be increased when it is combined with Artemether.
EfavirenzThe serum concentration of Artemether can be decreased when it is combined with Efavirenz.
EnzalutamideThe serum concentration of the active metabolites of Artemether can be reduced when Artemether is used in combination with Enzalutamide resulting in a loss in efficacy.
EtonogestrelThe serum concentration of Etonogestrel can be decreased when it is combined with Artemether.
EtravirineThe serum concentration of the active metabolites of Artemether can be reduced when Artemether is used in combination with Etravirine resulting in a loss in efficacy.
FluvoxamineThe metabolism of Fluvoxamine can be decreased when combined with Artemether.
FosphenytoinThe serum concentration of the active metabolites of Artemether can be reduced when Artemether is used in combination with Fosphenytoin resulting in a loss in efficacy.
GoserelinGoserelin may increase the QTc-prolonging activities of Artemether.
HydroxychloroquineThe risk or severity of adverse effects can be increased when Artemether is combined with Hydroxychloroquine.
LeuprolideLeuprolide may increase the QTc-prolonging activities of Artemether.
LevonorgestrelThe serum concentration of Levonorgestrel can be decreased when it is combined with Artemether.
Medroxyprogesterone acetateThe serum concentration of Medroxyprogesterone Acetate can be decreased when it is combined with Artemether.
MefloquineThe risk or severity of adverse effects can be increased when Artemether is combined with Mefloquine.
MitotaneThe serum concentration of the active metabolites of Artemether can be reduced when Artemether is used in combination with Mitotane resulting in a loss in efficacy.
NelfinavirThe serum concentration of Artemether can be increased when it is combined with Nelfinavir.
NevirapineThe serum concentration of Artemether can be decreased when it is combined with Nevirapine.
NorethisteroneThe serum concentration of Norethindrone can be decreased when it is combined with Artemether.
OctreotideOctreotide may increase the QTc-prolonging activities of Artemether.
PhenobarbitalThe serum concentration of the active metabolites of Artemether can be reduced when Artemether is used in combination with Phenobarbital resulting in a loss in efficacy.
PhenytoinThe serum concentration of the active metabolites of Artemether can be reduced when Artemether is used in combination with Phenytoin resulting in a loss in efficacy.
PrimaquineThe risk or severity of adverse effects can be increased when Artemether is combined with Primaquine.
PrimidoneThe serum concentration of the active metabolites of Artemether can be reduced when Artemether is used in combination with Primidone resulting in a loss in efficacy.
PyrimethamineThe risk or severity of adverse effects can be increased when Artemether is combined with Pyrimethamine.
QuinineThe risk or severity of adverse effects can be increased when Artemether is combined with Quinine.
RifabutinThe serum concentration of the active metabolites of Artemether can be reduced when Artemether is used in combination with Rifabutin resulting in a loss in efficacy.
RifampicinThe serum concentration of the active metabolites of Artemether can be reduced when Artemether is used in combination with Rifampicin resulting in a loss in efficacy.
RifapentineThe serum concentration of the active metabolites of Artemether can be reduced when Artemether is used in combination with Rifapentine resulting in a loss in efficacy.
St. John's WortThe serum concentration of the active metabolites of Artemether can be reduced when Artemether is used in combination with St. John's Wort resulting in a loss in efficacy.
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

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinducer
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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Oxygen binding
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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP3A5
Uniprot ID:
P20815
Molecular Weight:
57108.065 Da
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinducer
General Function:
Steroid 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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,4-cineole 2-exo-monooxygenase.
Gene Name:
CYP2B6
Uniprot ID:
P20813
Molecular Weight:
56277.81 Da
References
  1. 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. doi: 10.1007/s10928-008-9084-6. Epub 2008 Mar 19. [PubMed:18350255 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid 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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular Weight:
55627.365 Da
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinducer
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine.
Gene Name:
CYP2C19
Uniprot ID:
P33261
Molecular Weight:
55930.545 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
  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. doi: 10.1007/s10928-008-9084-6. Epub 2008 Mar 19. [PubMed:18350255 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
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Drug created on May 05, 2010 12:03 / Updated on September 16, 2013 18:04