Identification

Name
Artesunate
Accession Number
DB09274
Description

Artesunate is indicated for the initial treatment of severe malaria.8 The World Health Organization recommends artesunate as first line treatment for severe malaria.6 Artesunate was developed out of a need for a more hydrophilic derivative of artemisinin.5

Artesunate was granted FDA approval on 26 May 2020.8

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 384.425
Monoisotopic: 384.178417862
Chemical Formula
C19H28O8
Synonyms
  • Artesunate
  • Artesunato
  • Artesunatum
  • Artesunic acid
  • AS
  • butanedioic acid, 1-[(3R,5aS,6R,8aS,9R,10S,12R,12aR)-decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-yl] ester
  • dihydroqinghasu hemsuccinate
  • Succinyl dihydroartemisinin
External IDs
  • 182824-33-5
  • NSC-712571

Pharmacology

Indication

Artesunate is indicated for the initial treatment of severe malaria in adult and pediatric patients.8

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Artesunate is an artemisinin derivative that is metabolized to DHA, which generates free radicals to inhibit normal function of Plasmodium parasites.1,7,8 It has a short duration of action due to its short half life, and a moderate therapeutic index.7,8 Patients should be counselled regarding the risk of post treatment hemolytic anemia and hypersenstivity.8

Mechanism of action

Artesunate is metabolized to the active DHA.8 the endoperoxide bridge of DHA reacts with heme, generating free radicals which inhibit protein and nucleic acid synthesis of the Plasmodium parasites during all erythrocytic stages.8,7 Reactions with these free radicals can also lead to alkylation of parasitic proteins such as a calcium adenosine triphosphatase and EXP1, a glutathione S-transferase.1,7

TargetActionsOrganism
AMalaria protein EXP-1
inhibitor
Plasmodium falciparum
Absorption

The Cmax of artesunate is 3.3µg/mL while the Cmax of the active metabolite DHA is 3.1µg/mL.8 The AUC of artesunate is 0.7µg*h/mL while the AUC of DHA is 3.5µg*h/mL.8 After intravenous artesunate, DHA has a Tmax of 0.5-15 minutes in adult patients and 21-64 minutes in pediatric patients.7 Intramuscular artesunate has a Tmax of 8-12 minutes.7 Infants less than 6 months old will have a higher AUC due to an undeveloped UGT metabolic pathway.8

Volume of distribution

The volume of distribution of artesunate is 68.5L while the volume of distribution of DHA is 59.7L.8

Protein binding

Artesunate and its metabolite DHA are approximately 93% protein bound in plasma.8 Artesunate can bind to serum albumin.4

Metabolism

Artesunate is rapidly metabolized to dihydroartemisinin (DHA) by plasma esterases.8 DHA is glucuronidated by UGT1A9 and UGT2B7 to DHA-glucuronide.2,8 DHA-glucuronide can undergo a minor metabolic pathway to for a furano acetate derivative of DHA-glucuronide.2 CYP2A6 may minorly contribute to the metabolism of artesunate.7

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Route of elimination

The main route of elimination in humans is unknown.8 In rats, a dose of artesunate is 56.1% eliminated in the urine and 38.5% in the feces.3

Half-life

The elimination half life of artesunate is 0.3h with a range of 0.1-1.8h.8 The elimination half life of DHA is 1.3h with a range of 0.9-2.9h.8 Half life after intramuscular administration is 48 min in children and 41 min in adults.7

Clearance

The clearance of artesunate is 180L/h while the clearance of DHA is 32.3L/h.8

Adverse Effects
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Toxicity

Data regarding overdoses of artesunate are rare.8 Patients experiencing an overdose may present with pancytopenia, melena, seizures, multiorgan failure, and death.8 Treat overdose with symptomatic and supportive measures.8

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

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcetophenazineThe risk or severity of QTc prolongation can be increased when Artesunate is combined with Acetophenazine.
AlimemazineThe risk or severity of QTc prolongation can be increased when Artesunate is combined with Alimemazine.
ArtemetherThe risk or severity of QTc prolongation can be increased when Artesunate is combined with Artemether.
ButaperazineThe risk or severity of QTc prolongation can be increased when Artesunate is combined with Butaperazine.
Chenodeoxycholic acidThe metabolism of Artesunate can be decreased when combined with Chenodeoxycholic acid.
ChlorpromazineThe risk or severity of QTc prolongation can be increased when Artesunate is combined with Chlorpromazine.
DapsoneThe risk or severity of adverse effects can be increased when Artesunate is combined with Dapsone.
Darbepoetin alfaThe risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Artesunate.
DeferasiroxThe metabolism of Artesunate can be decreased when combined with Deferasirox.
DiflunisalThe metabolism of Artesunate can be decreased when combined with Diflunisal.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
No interactions found.

Products

Product Ingredients
IngredientUNIICASInChI Key
Artesunate sodiumCN5E49Z61182864-68-4ZISJLHQNEVGTIU-RFEYTNPVSA-M

Categories

ATC Codes
P01BE03 — ArtesunateP01BF02 — Artesunate and mefloquineP01BF03 — Artesunate and amodiaquineP01BF06 — Artesunate and pyronaridineP01BF04 — Artesunate, sulphamethopyrazine and pyrimethamine
Drug Categories
Chemical TaxonomyProvided by Classyfire
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 / Heterocyclic fatty acids / Fatty acid esters / Trioxanes / Oxanes / Dicarboxylic acids and derivatives / Dialkyl peroxides / Carboxylic acid esters / Oxacyclic compounds / Carboxylic acids
show 3 more
Substituents
1,2,4-trioxane / Acetal / Aliphatic heteropolycyclic compound / Artemisinin skeleton / Carbonyl group / Carboxylic acid / Carboxylic acid derivative / Carboxylic acid ester / Dialkyl peroxide / Dicarboxylic acid or derivatives
show 11 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
dicarboxylic acid monoester, semisynthetic derivative, sesquiterpenoid, artemisinin derivative, cyclic acetal (CHEBI:63918)

Chemical Identifiers

UNII
60W3249T9M
CAS number
88495-63-0
InChI Key
FIHJKUPKCHIPAT-AHIGJZGOSA-N
InChI
InChI=1S/C19H28O8/c1-10-4-5-13-11(2)16(23-15(22)7-6-14(20)21)24-17-19(13)12(10)8-9-18(3,25-17)26-27-19/h10-13,16-17H,4-9H2,1-3H3,(H,20,21)/t10-,11-,12+,13+,16-,17-,18-,19-/m1/s1
IUPAC Name
4-oxo-4-{[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0⁴,¹³.0⁸,¹³]hexadecan-10-yl]oxy}butanoic acid
SMILES
[H][C@@]12CC[C@@H](C)[C@]3([H])CC[C@@]4(C)OO[C@@]13[C@]([H])(O[C@@H](OC(=O)CCC(O)=O)[C@@H]2C)O4

References

General References
  1. Lisewski AM, Quiros JP, Ng CL, Adikesavan AK, Miura K, Putluri N, Eastman RT, Scanfeld D, Regenbogen SJ, Altenhofen L, Llinas M, Sreekumar A, Long C, Fidock DA, Lichtarge O: Supergenomic network compression and the discovery of EXP1 as a glutathione transferase inhibited by artesunate. Cell. 2014 Aug 14;158(4):916-28. doi: 10.1016/j.cell.2014.07.011. [PubMed:25126794]
  2. Ilett KF, Ethell BT, Maggs JL, Davis TM, Batty KT, Burchell B, Binh TQ, Thu le TA, Hung NC, Pirmohamed M, Park BK, Edwards G: Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab Dispos. 2002 Sep;30(9):1005-12. doi: 10.1124/dmd.30.9.1005. [PubMed:12167566]
  3. Li Q, Xie LH, Haeberle A, Zhang J, Weina P: The evaluation of radiolabeled artesunate on tissue distribution in rats and protein binding in humans. Am J Trop Med Hyg. 2006 Nov;75(5):817-26. [PubMed:17123971]
  4. Veerappan A, Eichhorn T, Zeino M, Efferth T, Schneider D: Differential interactions of the broad spectrum drugs artemisinin, dihydroartemisinin and artesunate with serum albumin. Phytomedicine. 2013 Aug 15;20(11):969-74. doi: 10.1016/j.phymed.2013.04.003. Epub 2013 May 16. [PubMed:23684544]
  5. White NJ, Hien TT, Nosten FH: A Brief History of Qinghaosu. Trends Parasitol. 2015 Dec;31(12):607-610. doi: 10.1016/j.pt.2015.10.010. [PubMed:26776328]
  6. CDC: Artesunate [Link]
  7. Artesunate Product Information [Link]
  8. FDA Approved Drug Products: Artesunate Intravenous Injection [Link]
Human Metabolome Database
HMDB0240267
KEGG Drug
D02482
PubChem Compound
6917864
PubChem Substance
310265169
ChemSpider
5293084
RxNav
18346
ChEBI
63918
ChEMBL
CHEMBL361497
ZINC
ZINC000014096305
PDBe Ligand
D95
Wikipedia
Artesunate
PDB Entries
6fgc
FDA label
Download (360 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingPreventionParasitic Diseases / Plasmodium Infections1
4Active Not RecruitingTreatmentPlasmodium Infections2
4CompletedNot AvailableHealthy Volunteers1
4CompletedNot AvailableMalaria caused by Plasmodium falciparum / Malaria Falciparum1
4CompletedHealth Services ResearchPlasmodium Infections1
4CompletedPreventionPlasmodium Infections1
4CompletedTreatmentAnemia1
4CompletedTreatmentFalciparum / Plasmodium Infections1
4CompletedTreatmentMalaria (Uncomplicated)1
4CompletedTreatmentMalaria caused by Plasmodium falciparum5

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)131-135MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.678 mg/mLALOGPS
logP2.35ALOGPS
logP3.1ChemAxon
logS-2.8ALOGPS
pKa (Strongest Acidic)3.77ChemAxon
pKa (Strongest Basic)-4.2ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area100.52 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity89.95 m3·mol-1ChemAxon
Polarizability39.46 Å3ChemAxon
Number of Rings4ChemAxon
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

Targets

Kind
Protein
Organism
Plasmodium falciparum
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
Not Available
Gene Name
EXP-1
Uniprot ID
P04926
Uniprot Name
Malaria protein EXP-1
Molecular Weight
17449.565 Da
References
  1. Lisewski AM, Quiros JP, Ng CL, Adikesavan AK, Miura K, Putluri N, Eastman RT, Scanfeld D, Regenbogen SJ, Altenhofen L, Llinas M, Sreekumar A, Long C, Fidock DA, Lichtarge O: Supergenomic network compression and the discovery of EXP1 as a glutathione transferase inhibited by artesunate. Cell. 2014 Aug 14;158(4):916-28. doi: 10.1016/j.cell.2014.07.011. [PubMed:25126794]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
Gene Name
UGT2B7
Uniprot ID
P16662
Uniprot Name
UDP-glucuronosyltransferase 2B7
Molecular Weight
60694.12 Da
References
  1. Ilett KF, Ethell BT, Maggs JL, Davis TM, Batty KT, Burchell B, Binh TQ, Thu le TA, Hung NC, Pirmohamed M, Park BK, Edwards G: Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab Dispos. 2002 Sep;30(9):1005-12. doi: 10.1124/dmd.30.9.1005. [PubMed:12167566]
  2. FDA Approved Drug Products: Artesunate Intravenous Injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. Ilett KF, Ethell BT, Maggs JL, Davis TM, Batty KT, Burchell B, Binh TQ, Thu le TA, Hung NC, Pirmohamed M, Park BK, Edwards G: Glucuronidation of dihydroartemisinin in vivo and by human liver microsomes and expressed UDP-glucuronosyltransferases. Drug Metab Dispos. 2002 Sep;30(9):1005-12. doi: 10.1124/dmd.30.9.1005. [PubMed:12167566]
  2. FDA Approved Drug Products: Artesunate Intravenous Injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const...
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
Molecular Weight
56501.005 Da
References
  1. Phompradit P, Muhamad P, Cheoymang A, Na-Bangchang K: Preliminary investigation of the contribution of CYP2A6, CYP2B6, and UGT1A9 polymorphisms on artesunate-mefloquine treatment response in Burmese patients with Plasmodium falciparum malaria. Am J Trop Med Hyg. 2014 Aug;91(2):361-6. doi: 10.4269/ajtmh.13-0531. Epub 2014 Jun 2. [PubMed:24891466]
  2. Artesunate Product Information [Link]
  3. Artesunate and Amiodiquine FDA Label [File]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Veerappan A, Eichhorn T, Zeino M, Efferth T, Schneider D: Differential interactions of the broad spectrum drugs artemisinin, dihydroartemisinin and artesunate with serum albumin. Phytomedicine. 2013 Aug 15;20(11):969-74. doi: 10.1016/j.phymed.2013.04.003. Epub 2013 May 16. [PubMed:23684544]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: Artesunate Intravenous Injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: Artesunate Intravenous Injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. FDA Approved Drug Products: Artesunate Intravenous Injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. FDA Approved Drug Products: Artesunate Intravenous Injection [Link]

Drug created on October 28, 2015 15:21 / Updated on June 12, 2020 11:42

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