Both MCF-7 and MDA-MB-231 cells are cytotoxic to triclabendazole (20-320 μM, 24-48 h) [1]. MCF-7 and MDA-MB-231 cells undergo apoptosis when exposed to triclabendazole (40–160 μM, 24 h) [1]. The cytotoxicity of trimetazole (0.97-500 μM, 48-72 h) on macrophages is minimal [3]. Proflagellated cells' cell cycle stages are significantly altered by triclabendazole (45.67 μM, 72 h) [3].

In nude mice implanted with MDA-MB-231 cells, trimethobenzole (20–100 mg/kg, intraperitoneal injection, twice weekly for 2 weeks) has antitumor activity [1].

Cell Cytotoxicity Assay[1]
Cell Types: MCF-7 and MDA-MB-231 cells
Tested Concentrations: 20 μM, 40 μM, 80 μM, 160 μM, 320 μM,
Incubation Duration: 24 h, 48 h
Experimental Results: Dramatically diminished the metabolism activity.

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Apoptosis Analysis[1]
Cell Types: MCF-7 and MDA-MB-231 cells
Tested Concentrations: 40 μM, 80 μM, 160 μM
Incubation Duration: 24 h
Experimental Results: Dramatically induced apoptosis at 160 μM. Up-regulated the expression of Bax and down-regulated the expression of Bcl-2. Activated and cleaved caspase-8 and caspase-9 in a dose-dependent manner.

Absorption, Distribution and Excretion
After a single oral dose of 10 mg/kg triclabendazole with a 560-kcal meal to patients diagnosed with fascioliasis, mean peak plasma concentrations (Cmax) for triclabendazole, the sulfoxide, and sulfone metabolites were 1.16, 38.6, and 2.29 μmol/L, respectively. The area under the curve (AUC) for triclabendazole, the sulfoxide and sulfone metabolites were 5.72, 386, and 30.5 μmol∙h/L, respectively. After the oral administration of a single dose of triclabendazole at 10 mg/kg with a 560 calorie meal to patients with fascioliasis, the median Tmax for the parent compound as well as the active sulfoxide metabolite was 3 to 4 hours. **Effect of Food** Cmax and AUC of triclabendazole and sulfoxide metabolite increased about 2-3 times when triclabendazole was administered as a single dose at 10 mg/kg with a meal containing approximately 560 calories. Additionally, the sulfoxide metabolite Tmax increased from 2 hours in fasting subjects to 4 hours in fed subjects.
No data regarding excretion is available in humans. In animals, triclabendazole is primarily excreted by the biliary tract in the feces (90%), together with the sulfoxide and sulfone metabolite. Less than 10% of an oral dose is found excreted in the urine.
The apparent volume of distribution (Vd) of the sulfoxide metabolite in fed patients is about 1 L/kg.

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Metabolism / Metabolites
Based on in vitro studies, triclabendazole is mainly metabolized by CYP1A2 enzyme (approximately 64%) into its active _sulfoxide_ metabolite and to a lesser extent by CYP2C9, CYP2C19, CYP2D6, CYP3A, and FMO (flavin containing monooxygenase). This sulfoxide metabolite is further metabolized mainly by CYP2C9 to the active sulfone metabolite, and to a smaller extent by CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, and CYP3A4, _in vitro_.

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Biological Half-Life
The plasma elimination half-life (t1/2) of triclabendazole, the sulfoxide and sulfone metabolites in human is about 8, 14, and 11 hours, respectively.

Hepatotoxicity
The published and historic controlled trials of triclabendazole in chronic fascioliasis rarely described adverse event rates or blood test results except for eosinophilia. Instances of enzyme elevations and jaundice have been described, but patients with chronic fascioliasis often have minor elevations in liver tests. Furthermore, the common side effects of treatment are most likely due to the effects of sudden expulsion of the liver flukes from the biliary tree, which can result in transient serum ALT and alkaline phosphatase elevations and even jaundice. There are no reports of serious liver injury, acute liver failure, vanishing bile duct syndrome or chronic hepatitis after triclabendazole therapy. There are reports of cholestatic hepatic injury and vanishing bile duct syndrome linked to other benzimidazole anthelmintic agents such as thiabendazole and albendazole. There is also reported association between Fasciola infection with the potential for bile duct obstruction and sequelae.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of triclabendazole during breastfeeding. Because of protein binding of 96% to 99% for the drug and metabolites, exposure of the breastfed infant is likely to be low.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Protein-binding of triclabendazole, sulfoxide metabolite and sulfone metabolite in human plasma was 96.7%, 98.4% and 98.8% respectively.

[1]. Yan L, et al. Triclabendazole induces pyroptosis by activating caspase-3 to cleave GSDME in breast cancer cells [J]. Frontiers in Pharmacology, 2021, 12: 670081.
[2]. Devine C, et al. Potentiation of triclabendazole action in vivo against a triclabendazole-resistant isolate of Fasciola hepatica following its co-administration with the metabolic inhibitor, ketoconazole [J]. Veterinary parasitology, 2012, 184(1): 37-47.
[3]. Borges B S, et al. In vitro anti-Leishmania activity of triclabendazole and its synergic effect with amphotericin B [J]. Frontiers in Cellular and Infection Microbiology, 2023, 12: 1044665.

6-chloro-5-(2,3-dichlorophenoxy)-2-(methylthio)-1H-benzimidazole is an aromatic ether.
Triclabendazole, manufactured by Novartis pharmaceuticals, is an antihelminthic drug that was approved by the FDA in February 2019 for the treatment of fascioliasis in humans. Fascioliasis is a parasitic infection often caused by the helminth, Fasciola hepatica, which is also known as “the common liver fluke” or “the sheep liver fluke” or by Fasciola gigantica, another helminth. These parasites can infect humans following ingestion of larvae in contaminated water or food. Triclabendazole was previously used in the treatment of fascioliasis in livestock, but is now approved for human use. This drug is currently the only FDA-approved drug for individuals with fascioliasis, which affects 2.4 million people worldwide.
Triclabendazole is an Anthelmintic. The mechanism of action of triclabendazole is as a Cytochrome P450 2C19 Inhibitor, and Cytochrome P450 1A2 Inhibitor, and Cytochrome P450 2A6 Inhibitor, and Cytochrome P450 2B6 Inhibitor, and Cytochrome P450 2C8 Inhibitor, and Cytochrome P450 2C9 Inhibitor, and Cytochrome P450 2D6 Inhibitor, and Cytochrome P450 3A Inhibitor.
Triclabendazole is an oral anthelmintic used in the treatment of chronic fascioliasis. Triclabendazole therapy is generally well tolerated but can be accompanied by abdominal pain, nausea and mild liver test abnormalities, which are probably due to the expulsion of dead or dying flukes rather than hepatic injury due to the therapy.
Benzimidazole antiplatyhelmintic agent that is used for the treatment of FASCIOLIASIS and PARAGONIMIASIS.

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Drug Indication
This drug is indicated for the treatment of fascioliasis in patients aged 6 years old and above.
FDA Label

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Mechanism of Action
Triclabendazole is an anthelmintic agent against _Fasciola_ species. The mechanism of action against Fasciola species is not fully understood at this time. In vitro studies and animal studies suggest that triclabendazole and its active metabolites (_sulfoxide_ and _sulfone_) are absorbed by the outer body covering of the immature and mature worms, causing a reduction in the resting membrane potential, the inhibition of tubulin function as well as protein and enzyme synthesis necessary for survival. These metabolic disturbances lead to an inhibition of motility, disruption of the worm outer surface, in addition to the inhibition of spermatogenesis and egg/embryonic cells. **A note on resistance** In vitro studies, in vivo studies, as well as case reports suggest a possibility for the development of resistance to triclabendazole. The mechanism of resistance may be multifactorial and include changes in drug uptake/efflux mechanisms, target molecules, and changes in drug metabolism. The clinical significance of triclabendazole resistance in humans is not yet elucidated.

C14H9CL3N2OS

359.66

357.95

68786-66-3

Triclabendazole-d3;1353867-93-2;Triclabendazole-13C,d3

50248

Typically exists as solid at room temperature

1.6±0.1 g/cm3

495.9±55.0 °C at 760 mmHg

175-176°C

253.7±31.5 °C

0.0±1.3 mmHg at 25°C

1.724

5.97

1

3

3

21

365

0

ClC1C([H])=C2C(=C([H])C=1OC1C([H])=C([H])C([H])=C(C=1Cl)Cl)N=C(N2[H])SC([H])([H])[H]

NQPDXQQQCQDHHW-UHFFFAOYSA-N

InChI=1S/C14H9Cl3N2OS/c1-21-14-18-9-5-8(16)12(6-10(9)19-14)20-11-4-2-3-7(15)13(11)17/h2-6H,1H3,(H,18,19)

6-Chloro-5-(2,3-dichlorophenoxy)-2-methylsulfanyl-1H-benzimidazole

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: ≥ 2.5 mg/mL (6.95 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 25.0 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 (5.78 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 (5.78 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.)