Artesunate inhibits exportin 1 (EXP1)[2] and STAT-3[1]. Both cell lines showed a notable dose-dependent rise in reactive oxygen species (ROS) following a 24-hour treatment with artesunate. Furthermore, artesunate treatment of cancer cells at greater doses for 24 hours was found to considerably raise γ-H2AX levels, as demonstrated by Western blotting. Additionally, in A2780 and HO8910 cells, artesunate exhibited time-dependent impacts on RAD51 levels. Two types of non-malignant cells (normal human fibroblasts and immortalized epithelial cells FTE-187) showed no change in RAD51 levels in response to artesunate. In fact, artesunate decreased RAD51 mRNA levels in A2780 cells in a dose-dependent way. Correspondingly, artesunate markedly reduced the promoter activity of RAD51. In contrast, artesunate had no effect on the amounts of RAD51 mRNA in H8910 cells [3].

In the group receiving combined treatment with artesunate and cisplatin, tumor development was considerably inhibited (P<0.01). On the other hand, neither cell line's tumor xenografts grew significantly when artesunate was used alone [3].

Absorption, Distribution and Excretion
The Cmax of artesunate is 3.3µg/mL while the Cmax of the active metabolite DHA is 3.1µg/mL. The AUC of artesunate is 0.7µg\*h/mL while the AUC of DHA is 3.5µg\*h/mL. After intravenous artesunate, DHA has a Tmax of 0.5-15 minutes in adult patients and 21-64 minutes in pediatric patients. Intramuscular artesunate has a Tmax of 8-12 minutes. Infants less than 6 months old will have a higher AUC due to an undeveloped UGT metabolic pathway.
The main route of elimination in humans is unknown. In rats, a dose of artesunate is 56.1% eliminated in the urine and 38.5% in the feces.
The volume of distribution of artesunate is 68.5L while the volume of distribution of DHA is 59.7L.
The clearance of artesunate is 180L/h while the clearance of DHA is 32.3L/h.
Following administration to humans, artesunate is rapidly hydrolyzed to its principal active metabolite, dihydroartemisinin. The pharmacokinetics of artesunate are characterized by marked inter-subject variability, differing significantly between healthy volunteers and infected patients, and among patients with different disease severity.
The pharmacokinetic of artesunate and dihydroartemisin are characterized by marked inter-subject variability. The pharmacokinetic parameters of artesunate and dihydroartemisinin differ significantly between healthy volunteers and infected patients, and among patients with different disease severity. Pharmacokinetic data from unbound plasma concentrations of artesunate or dihydroartemisinin should be interpreted with caution because the drug accumulates selectively in parasitized RBC's In in vitro experiments, accumulation of dihydroartemisinin in infected RBC's is in concentrations approximately 300-fold higher than those in plasma .
The pharmacokinetics of oral dihydroartemisinin (DHA) following the dose of 2 and 4 mg/ kg body weight dihydroartemisinin and 4 mg/kg body weight oral artesunate (AS) were investigated in 20 healthy Thai volunteers (10 males, 10 females). All formulations were generally well tolerated. Oral DHA was rapidly absorbed from gastrointestinal tract with marked inter-individual variation. The pharmacokinetics of DHA following the two dose levels were similar and linearity in its kinetics was observed. Based on the model-independent pharmacokinetic analysis, median (95% CI) values for Cmax of 181 (120-306) and 360 (181-658) ng/ml were achieved at 1.5 hours following 2 and 4 mg/kg body weight dose, respectively. The corresponding values for AUC0-infinity, t1/2z, CL/f and Vz/f were 377 (199-1,128) vs 907 (324-2,289) ng.hr/mL, 0.96 (0.70-1.81) vs 1.2 (0.75-1.44) hours, 7.7 (4.3-12.3) vs 6.6 (3.1-10.1) L/kg, and 90.5 (28.6-178.2) vs 6.6 (3.1-10.1) mL/min/kg, respectively (2 vs 4 mg/kg dose). Oral AS was rapidly biotransformed to DHA, which was detectable in plasma as early as 15 minutes of AS dosing. Following 4 mg/kg dose, median (95% CI) value for Cmax of 519 (236-284) ng/mL was achieved at 0.7 (0.25-1.5) hours. AUC0-infinity, and t1/2z were 657 (362-2,079) ng.hr/mL, 0.74 (0.34-1.42) hours, respectively. Cmax of DHA following oral AS were significantly higher, but total systemic exposure was greater following oral DHA at the same dose level (4 mg/kg body weight). There was no significant sex difference in pharmacokinetics of DHA
The aims of this study were to determine the pharmacokinetic parameters of a single dose of 200 mg oral and rectal artesunate in healthy volunteers, and to suggest a rational dosage regimen for rectal administration. The study design was a randomized open cross-over study of 12 healthy volunteers... Pharmacokinetic parameters were derived from the main metabolite alpha-dihydroartemisinin data due to the rapid disappearance of artesunate from the plasma. Dihydroartemisinin following oral administration of artesunate had a significantly higher AUC(0-infinity) (P<0.05 95% confidence interval (CI) -1168.73, -667.61 ng x hr/mL(-1)) and Cmax (P<0.05; 95% CI -419.73, -171.44 ng/mL(-1)), and had shorter tmax (P<0.05; 95% CI -0.97, -0.10 hr) than that following rectal artesunate. There was no statistically significant difference in the elimination half-life between both routes of administration (P>0.05; 95% CI -0.14, 0.53 hr). The relative bioavailability of rectal artesunate was [mean (coefficient of variation %) 54.9 (24.8%) %].
For more Absorption, Distribution and Excretion (Complete) data for ARTESUNIC ACID (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Artesunate is rapidly metabolized to dihydroartemisinin (DHA) by plasma esterases. DHA is glucuronidated by UGT1A9 and UGT2B7 to DHA-glucuronide. DHA-glucuronide can undergo a minor metabolic pathway to for a furano acetate derivative of DHA-glucuronide. CYP2A6 may minorly contribute to the metabolism of artesunate.
Following administration to humans, artesunate is rapidly hydrolyzed to its principle active metabolite, dihydroartemisinin. Data from in vitro studies with human liver microsomes and from clinical studies suggest that DHA-glucoronide (10-position) is the principal Phase II metabolite of DHA and that uridine diphosphate glucuronyl transferase isoforms 1A1, 1A8-9, or 2B7 may be the main conjugating enzyme.
Artemisinin is completely and rapidly absorbed after oral administration in rats. However, a very low plasma level was obtained even after a dose of 300 mg/kg. Liver was found to be the chief site of inactivation. When artemisinin was given i.m., significant and more persistent plasma levels were detected. Artemisinin was shown to pass the blood-brain and blood-placenta barriers after i.v. injection. Very little unchanged artemisinin was found in the urine or feces in 48 hours regardless of the route of administration. Metabolites identified after administration to humans include deoxyartemisinin, deoxydihydroartemisinin, and 9,10-dihydroxydeoxyartemisinin.
Artesunate has known human metabolites that include (1S,4S,5R,8S,9R,10R,12R,13R)-1,5,9-Trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-ol.

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Biological Half-Life
The elimination half life of artesunate is 0.3h with a range of 0.1-1.8h. The elimination half life of DHA is 1.3h with a range of 0.9-2.9h. Half life after intramuscular administration is 48 min in children and 41 min in adults.
In volunteer studies, artsunate was cleared very rapidly (within minutes) by biotransformation to dihydroartemisinin, which was eliminated by with a half-life of approximately 45 minutes.

Hepatotoxicity
In an open label study of severe malaria in 104 patients in the United States, elevations in ALT occurred in 27% of subjects, AST in 49%, and bilirubin in 17%. These abnormalities, however, were attributable to the hemolysis and liver involvement that are common in patients with acute, severe malaria. None of the elevations were attributed to drug induced liver injury. Since licensure of artesunate for injection and its more widescale clinical use in the United States, there have been no reports of acute liver injury attributed to its use.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that a maternal dose of 200 mg orally produced low levels in milk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. Withholding breastfeeding for 6 hours after a dose should markedly reduce the dose the infant receives.
In general, very small amounts of antimalarial drugs are excreted in the breast milk of lactating women. Because the quantity of antimalarial drugs transferred in breast milk is insufficient to provide adequate protection against malaria, infants who require chemoprophylaxis must receive the recommended dosages of antimalarial drugs.
◉ Effects in Breastfed Infants
Breastfed infants who were given dihydroartemisinin and piperaquine as a treatment for malaria had a higher frequency of vomiting than non-breastfed infants given the drugs. Whether this finding applies to infants who receive dihydroartemisinin via breastmilk has not been studied.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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

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Interactions
The activity of artemisinin in combination with other antimalarial drugs against P. falciparum was measured in vitro and against P. berghei in vivo. A combination of artemisinin with mefloquine was synergistic whereas that with pyrimethamine was antagonistic in vitro and in vivo. A combination of artemisinin with other antimalarials (sulfadiazine, sulfadoxine, sulfadoxine-pyrimethamine, cycloguanil, and dapsone) was also shown to be antagonistic in vivo.
There has been some concern that antipyretics might attenuate the host defense against malaria, as their use is associated with delayed parasite clearance. However, this appears to result from delaying cytoadherence, which is likely to be beneficial. There is no reason to withhold antipyretics in malaria. ...Paracetamol (acetaminophen) and ibuprofen are the preferred options for reducing fever.

[1]. Ilamathi M, et al. Artesunate as an Anti-Cancer Agent Targets Stat-3 and Favorably Suppresses Hepatocellular Carcinoma. Curr Top Med Chem. 2016;16(22):2453-63.
[2]. Lisewski AM, et al. Supergenomic network compression and the discovery of EXP1 as a glutathione transferase inhibited by artesunate. Cell. 2014 Aug 14;158(4):916-928.
[3]. Wang B, et al. Artesunate sensitizes ovarian cancer cells to cisplatin by downregulating RAD51. Cancer Biol Ther. 2015;16(10):1548-56

Therapeutic Uses
Therap Cat: Antimalarial
Artesunate Rectal Capsules is indicated for the initial management of acute malaria in patients who cannot take medication by mouth and for whom parenteral treatment is not available.
To counter the threat of resistance of P. falciparum to monotherapies, and to improve treatment outcome, combinations of antimalarials are now recommended by WHO for the treatment of falciparum malaria. The following ACTs are currently recommended (alphabetical order): AS+AQ artesunate + amodiaquine combination, AS+MQ artesunate + mefloquine combination, AS+SP artesunate + sulfadoxine-pyrimethamine combination.
Artemisinin and its derivatives (artesunate, artemether, artemotil, dihydroartemisinin) produce rapid clearance of parasitaemia and rapid resolution of symptoms. They reduce parasite numbers by a factor of approximately 10,000 in each asexual cycle, which is more than other current antimalarials (which reduce parasite numbers 100- to 1000-fold per cycle). Artemisinin and its derivatives are eliminated rapidly. When given in combination with rapidly eliminated compounds (tetracyclines, clindamycin), a 7-day course of treatment with an artemisinin compound is required; but when given in combination with slowly eliminated antimalarials, shorter courses of treatment (3 days) are effective. The evidence of their superiority in comparison to monotherapies has been clearly documented.
For more Therapeutic Uses (Complete) data for ARTESUNIC ACID (14 total), please visit the HSDB record page.

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Drug Warnings
Artemisinin congeners should not be given to patients with a previous history of an allergic reaction following their consumption or if an urticarial rash develops during treatment. Patient with a history of hypersensitivity reaction to one of the artemsinins should be advised not to take any of the derivatives again.
Artesunate rectal capsules have not been evaluated as sole therapy for malaria; consequently all patient who are initially treated with artesunate rectal capsules should be promptly referred and evaluated at the nearest health care facility able to provide a full curative course of treatment for malaria.
Adverse events described /following artesunate/ included bitter taste, mild pain at the injection site, bradycardia, paroxysmal ventricular premature beat, incomplete right bundle branch block, first-degree atrio-ventricular block, and urticaria.
... The most commonly reported adverse events (in the order of <1%) to be mild gastrointestinal (nausea, vomiting, diarrhea, abdominal pain) events.
For more Drug Warnings (Complete) data for ARTESUNIC ACID (25 total), please visit the HSDB record page.

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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. It has a short duration of action due to its short half life, and a moderate therapeutic index. Patients should be counselled regarding the risk of post treatment hemolytic anemia and hypersenstivity.

C19H28O8

384.42

384.178

88495-63-0

Artesunate-d3;1316303-44-2;Artesunate-d4;1316753-15-7

6917864

Fine white crystalline powder

1.3±0.1 g/cm3

507.1±50.0 °C at 760 mmHg

132-135ºC

175.6±23.6 °C

0.0±2.8 mmHg at 25°C

1.544

2.94

1

8

5

27

623

8

C[C@H]1[C@H](OC(=O)CCC(=O)O)O[C@@H]2O[C@]3(CC[C@@H]4[C@@]2(OO3)[C@H]1CC[C@H]4C)C

FIHJKUPKCHIPAT-AHIGJZGOSA-N

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

4-oxo-4-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)butanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.41 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.41 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (5.41 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)