Identification

Name
Artemether
Accession Number
DB06697
Type
Small Molecule
Groups
Approved
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 IDs
SM 224
Product Images
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
CoartemArtemether (20 mg/1) + Lumefantrine (120 mg/1)TabletOralCentral Texas Community Health Centers2009-04-07Not applicableUs
CoartemArtemether (20 mg/1) + Lumefantrine (120 mg/1)TabletOralNovartis2009-04-07Not applicableUs00078 0568 45 nlmimage10 6c443641
CoartemArtemether (20 mg/1) + Lumefantrine (120 mg/1)TabletOralDepartment Of State Health Services, Pharmacy Branch2009-04-072018-02-28Us
Categories
UNII
C7D6T3H22J
CAS number
71963-77-4
Weight
Average: 298.3746
Monoisotopic: 298.178023942
Chemical Formula
C16H26O5
InChI Key
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[C@H](OC)[C@@H]2C)O4

Pharmacology

Indication

Artemether 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.

Associated Conditions
Pharmacodynamics

In 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 action

Involves 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.

Absorption

Food increases absorption.

Volume of distribution
Not Available
Protein binding

Artemether 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.

Route of elimination
Not Available
Half life

Artemether, 1.6 +/- 0.7 and 2.2 +/- 1.9 hr; Dihydroartemisinin, 1.6 +/- 0.6 and 2.2 +/- 1.5 hr

Clearance
Not Available
Toxicity

Animal 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
PathwayCategory
Artemether Metabolism PathwayDrug metabolism
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
4-MethoxyamphetamineThe metabolism of 4-Methoxyamphetamine can be decreased when combined with Artemether.
5'-Deoxy-5'-MethylthioadenosineThe risk or severity of QTc prolongation can be increased when 5'-Deoxy-5'-Methylthioadenosine is combined with Artemether.
AbirateroneThe serum concentration of Artemether can be increased when it is combined with Abiraterone.
AcepromazineThe serum concentration of Acepromazine can be increased when it is combined with Artemether.
AceprometazineThe serum concentration of Aceprometazine can be increased when it is combined with Artemether.
Acetyl sulfisoxazoleThe metabolism of Artemether can be decreased when combined with Acetyl sulfisoxazole.
AcetylcholineThe metabolism of Acetylcholine can be decreased when combined with Artemether.
AjmalineThe metabolism of Ajmaline can be decreased when combined with Artemether.
AlclometasoneThe metabolism of Alclometasone can be increased when combined with Artemether.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Artemether.
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.

References

Synthesis Reference

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
Human Metabolome Database
HMDB0015643
KEGG Drug
D02483
PubChem Compound
68911
PubChem Substance
99443251
ChemSpider
62138
BindingDB
50022886
ChEBI
195280
ChEMBL
CHEMBL566534
PharmGKB
PA165111698
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Artemether
ATC Codes
P01BF01 — Artemether and lumefantrineP01BE02 — Artemether
FDA label
Download (1.73 MB)
MSDS
Download (566 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers / Plasmodium Infections1
1CompletedHealth Services ResearchHuman Immunodeficiency Virus (HIV)1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Plasmodium Infections1
1CompletedTreatmentMalaria caused by Plasmodium falciparum1
1CompletedTreatmentMalaria caused by plasmodium vivax1
1Enrolling by InvitationPreventionPlasmodium Infections1
1RecruitingPreventionPlasmodium Infections1
1, 2RecruitingTreatmentTumors, Solid1
2Active Not RecruitingTreatmentPlasmodium Infections1
2CompletedTreatmentMalaria caused by Plasmodium falciparum1
2Not Yet RecruitingTreatmentPlasmodium Infections1
2RecruitingTreatmentAcute Uncomplicated Plasmodium Falciparum Malaria1
2RecruitingTreatmentPlasmodium Infections1
3Active Not RecruitingTreatmentPlasmodium Falciparum Infection1
3CompletedTreatmentMalaria caused by plasmodium vivax1
3CompletedTreatmentMalaria in Pregnancy1
3CompletedTreatmentPlasmodium Falciparum Malaria2
3CompletedTreatmentPlasmodium Infections11
3Unknown StatusTreatmentPlasmodium Infections1
4CompletedNot AvailablePlasmodium Infections1
4CompletedBasic ScienceHuman Immunodeficiency Virus (HIV) Infections1
4CompletedBasic SciencePlasmodium Falciparum Clinical Episode / Plasmodium Falciparum Infection / Plasmodium Vivax Clinical Episode / Plasmodium Vivax Infection1
4CompletedHealth Services ResearchAnemias / Plasmodium Infections / Pregnancy1
4CompletedOtherPlasmodium Infections1
4CompletedTreatmentFalciparum / Plasmodium Infections1
4CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Plasmodium Infections1
4CompletedTreatmentHuman Immunodeficiency Virus (HIV) / Plasmodium Infections1
4CompletedTreatmentInstantaneous Clearance1
4CompletedTreatmentMalaria caused by Plasmodium falciparum4
4CompletedTreatmentParasitologically Confirmed; Malarial1
4CompletedTreatmentPlasmodium Falciparum Malaria1
4CompletedTreatmentPlasmodium Infections9
4RecruitingTreatmentUncomplicated Plasmodium Falciparum Malaria1
4TerminatedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Plasmodium Infections1
4TerminatedTreatmentMalaria caused by Plasmodium falciparum1
4TerminatedTreatmentPlasmodium Infections1
4TerminatedTreatmentPlasmodium Vivax Malaria1
4Unknown StatusTreatmentHuman Immunodeficiency Virus (HIV) Infections / Tuberculosis1
4Unknown StatusTreatmentPlasmodium Infections2
4Unknown StatusTreatmentUncomplicated Falciparum Malaria1
4Unknown StatusTreatmentUncomplicated Malaria1
Not AvailableCompletedNot AvailableUncomplicated Malaria1
Not AvailableCompletedHealth Services ResearchPlasmodium Infections / Pneumonia1
Not AvailableCompletedOtherPlasmodium Infections1
Not AvailableCompletedTreatmentMalaria caused by Plasmodium falciparum1
Not AvailableCompletedTreatmentNon-malarial Febrile Illness / Plasmodium Infections1
Not AvailableCompletedTreatmentPlasmodium Infections2
Not AvailableCompletedTreatmentPlasmodium Infections / Pneumonia1
Not AvailableCompletedTreatmentUncomplicated Malaria2

Pharmacoeconomics

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

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)86-90Not 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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Download (7.86 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-03di-0950000000-2ae4d4c9200a42ec883d

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Prenol lipids
Sub Class
Sesquiterpenoids
Direct Parent
Artemisinins
Alternative Parents
Oxepanes / Trioxanes / Oxanes / Dialkyl peroxides / Oxacyclic compounds / Acetals / Hydrocarbon derivatives
Substituents
Artemisinin skeleton / Oxepane / 1,2,4-trioxane / Oxane / Dialkyl peroxide / Oxacycle / Organoheterocyclic compound / Acetal / Organic oxygen compound / Hydrocarbon derivative
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
semisynthetic derivative, sesquiterpenoid, artemisinin derivative, cyclic acetal, organic peroxide (CHEBI:195280)

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inducer
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. 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 un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Mutagonda RF, Kamuhabwa AAR, Minzi OMS, Massawe SN, Asghar M, Homann MV, Farnert A, Aklillu E: Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women. Malar J. 2017 Jul 3;16(1):267. doi: 10.1186/s12936-017-1914-9. [PubMed:28673292]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inducer
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 un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
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 un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inducer
Curator comments
There is limited data confirming enzyme induction of CYP2C19 in the literature [A16806, F1516].
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 im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
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]
  3. Giao PT, de Vries PJ: Pharmacokinetic interactions of antimalarial agents. Clin Pharmacokinet. 2001;40(5):343-73. doi: 10.2165/00003088-200140050-00003. [PubMed:11432537]
  4. Artemether FDA label [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
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]

Drug created on May 05, 2010 12:03 / Updated on September 17, 2018 20:58