Absorption, Distribution and Excretion
Ethionamide is almost completely absorbed after oral administration, with no significant first-pass metabolism. Bioavailability is approximately 100%. Less than 1% of the oral dose is excreted in the urine as ethionamide. Ethionamide is extensively metabolized into active and inactive metabolites. 93.5 L [Healthy Volunteer] It is rapidly absorbed from the gastrointestinal tract after oral administration. Bioavailability is approximately 100%. Ethionamide is almost completely absorbed after oral administration, with no significant first-pass metabolism. In fasting adults, after a single oral dose of 250 mg ethionamide film-coated tablets, the average peak plasma concentration of ethionamide was 2.16 mcg/mL, reached within 1 hour. In healthy adults, after a single oral dose of 250 mg ethionamide sugar-coated tablets (Trecator-SC; discontinued in the US), the average peak plasma concentration was 1.48 μg/mL, reached within 1.5 hours. Time to peak concentration: Approximately 1.8 hours; peak serum concentration after a single oral dose of 500 mg ethionamide: Approximately 2.2 μg/mL. For more complete data on the absorption, distribution, and excretion of ethionamides (11 in total), please visit the HSDB record page. Metabolism/Metabolites: Primarily metabolized in the liver. It is metabolized into the active metabolite sulfoxide and several inactive metabolites. The sulfoxide metabolite has been shown to have antibacterial activity against Mycobacterium tuberculosis. Ethionamide is extensively metabolized into active and inactive metabolites. Metabolism is thought to occur in the liver, and six metabolites have been isolated to date: 2-ethylisonicotinamide, carbonyl dihydropyridine, thiocarbonyl dihydropyridine, S-oxocarbamoyl dihydropyridine, 2-ethylthioisonicotinamide, and ethionamide sulfoxide. The sulfoxide metabolite has been shown to have antibacterial activity against Mycobacterium tuberculosis.

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Biological Half-Life
2 to 3 hours
After oral administration of 250 mg film-coated tablets, the plasma half-life of ethionamide is 1.92 hours.
Half-life: Approximately 2 to 3 hours.

Toxicity Summary
Identification: Ethionamide is a drug used to treat tuberculosis. Ethionamide is a yellow crystalline powder. Soluble in 1:30 ethanol. Slightly soluble in water. Slightly soluble in chloroform. Slightly soluble in ether. Soluble in methanol. Slightly soluble in propylene glycol. Indications: For the treatment of pulmonary and extrapulmonary tuberculosis, in combination with other anti-tuberculosis drugs (when resistance to first-line drugs develops). For the treatment of leprosy as part of a multidrug combination therapy. For the treatment of lung disease caused by Mycobacterium kansas and other atypical mycobacteria. Human Exposure: Major risks and target organs: The most common adverse reactions are gastrointestinal disturbances, including anorexia, nausea, vomiting, excessive salivation, metallic taste in the mouth, stomatitis, and diarrhea, as well as hepatitis. Central nervous system effects include dizziness, somnolence, headache, seizures, peripheral neuropathy, tremor, and paresthesia. There is currently no experience with acute overdose of ethionamide. One of its metabolites is similar to isoniazid; similar symptoms should be observed. Clinical effects summary: Gastrointestinal: anorexia, vomiting, stomatitis, diarrhea; Systemic: excessive salivation, metallic taste in mouth, hepatotoxicity. Central nervous system: depression, anxiety, or psychosis; Systemic: encephalopathy with pellagra-like symptoms, dizziness, drowsiness, headache, convulsions, peripheral neuropathy, tremor, paresthesia; Ocular: optic neuritis, optic atrophy, diplopia; Nasal: olfactory dysfunction; Ear: deafness; Endocrine system: hypothyroidism, gynecomastia, impotence, menorrhagia, hypoglycemia; Skin: hair loss, acne, severe allergic rash, photosensitive dermatitis; Hematologic system: thrombocytopenia; Skeletal system: rheumatic pain; Cardiovascular system: orthostatic hypotension. Contraindications: Ethionamide is contraindicated in pregnant women unless the benefits outweigh the potential risks. Women of childbearing age should use with caution. Contraindicated in patients with severe liver disease. Contraindicated in patients with severe allergies. Caution: Caution should be exercised when using ethionamide in patients with depression or other mental illnesses, chronic alcoholism, epilepsy, hypothyroidism, or diabetes. Route of Administration: Oral: This is the commonly used route of administration. Injection: Ethionamide hydrochloride has been used intravenously, but there is currently no commercial formulation available. Other: Ethionamide has been administered as a rectal suppository. Absorption: After oral administration, approximately 80% of the dose of ethionamide is rapidly absorbed from the gastrointestinal tract. Bioavailability after oral administration is approximately 100%. The relative bioavailability after rectal administration is 57.3% of that after oral administration. Distribution: Ethionamide is widely distributed throughout the body tissues and fluids. It crosses the placenta and penetrates the meninges, with concentrations in cerebrospinal fluid comparable to those in serum. Protein binding is low (10%). Biological Half-Life (by route of exposure): The half-life is 2 to 3 hours. Ethionamide is primarily metabolized in the liver to produce ethionamide sulfoxide, 2-ethylisonicotinic acid, and 2-ethylisonicotinamide. Sulfoxide is the main active metabolite. Elimination pathway: Less than 1% of the dose is excreted unchanged in the urine, with the remainder excreted as inactive metabolites. Mechanism of action: Toxicology: Given the structural similarity between the metabolite 2-methylisonicotinic acid and isoniazid, some studies suggest its toxicity is due to pyridoxine deficiency. Pharmacodynamics: Ethionamide inhibits mycolic acid synthesis and stimulates redox reactions. Treated cells lose their acid resistance. Both the drug and its sulfoxide metabolites are effective against Mycobacterium tuberculosis. 2-Ethylisonicotinic acid and 2-ethylisonicotinamide are not active metabolites. At therapeutic concentrations, it has antibacterial activity against Mycobacterium tuberculosis, but may have bactericidal activity at higher concentrations. It has bactericidal activity against Mycobacterium leprae. When used alone, resistance develops rapidly, and complete cross-resistance exists with prothionamide, thiazolidinediones, and thiobutyronitrile. Toxicity: Adults: Neuropsychiatric symptoms such as headache, somnolence, insomnia, depression, and paresthesia may occur in clinical use. Elevated liver transaminases are known to occur. Since the dosage is adjusted according to patient response, no special precautions are required based on age. However, the dosage should be adjusted according to liver and kidney function. Interactions: Concomitant use of ethionamide and pyrazinamide may cause liver dysfunction; these two drugs should be avoided concurrently. The incidence of hepatotoxicity is unusually high when rifampin is used in combination with thioamides (ethionamide or prothionamide) to treat polybacillary leprosy. Adverse neurological effects of ethionamide, cycloserine, and isoniazid may have an additive effect. The side effects of ethionamide may be enhanced when used in combination with other antituberculosis drugs. Alcohol may induce psychiatric reactions in patients treated with ethionamide. Further research is needed to elucidate the clinical significance of this interaction. Major adverse reactions: The most common adverse reactions are dose-related and include: gastrointestinal disturbances such as anorexia, excessive salivation, metallic taste in the mouth, nausea, vomiting, stomatitis, diarrhea, and hepatitis. Occasionally, dizziness, drowsiness, headache, orthostatic hypotension, and fatigue are reported. Other reported side effects include acne, allergic reactions, hair loss, seizures, deafness, dermatitis (including photosensitive dermatitis), visual disturbances, tremor, gynecomastia, impotence, menstrual disorders, olfactory disturbances, peripheral neuropathy and optic neuropathy, thrombocytopenia, and rheumatic pain. Mental disorders (including depression, anxiety, and psychosis) have been reported. Rare case reports of pellagra-like encephalopathy syndromes have been reported. A tendency towards hypoglycemia may occur, which is particularly important in diabetic patients. Hypothyroidism has also been reported. Tolerance may vary among different ethnic groups; for example, Chinese and Africans generally tolerate ethionamide better than Europeans. Animal/Plant Studies: A rat study showed that ethionamide has sublethal neurotoxicity, including paralysis, decreased grip strength, and reduced motor function. Teratogenicity: Ethionamide has been reported to be teratogenic in rabbits, mice, and rats; high doses can lead to miscarriage and some birth defects. Mutagenicity: Ames Salmonella assay and micronucleus assay showed that ethionamide is not mutagenic.

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Hepatotoxicity
Ethionamide treatment is associated with elevated serum transaminase levels in some patients, but these elevations are usually self-limiting and asymptomatic. More importantly, ethionamide is associated with many clinically significant cases of acute liver injury, with an incidence of up to 5%, and the condition can be severe and even fatal. The onset and clinical characteristics of ethionamide-induced liver injury are similar to those of isoniazid, with incubation periods ranging from 2 weeks to more than 6 months after the start of treatment (most appearing within 1 to 3 months). The pattern of enzyme elevation is usually hepatocellular, similar to acute viral hepatitis. Hypersensitivity reactions (rash, fever, and eosinophilia) are uncommon. Similar to isoniazid, ethionamide treatment may be associated with the production of autoantibodies (usually antinuclear antibodies, ANA), but titers are typically low and rarely associated with autoimmune diseases. Case reports of severe hypersensitivity reactions to ethionamide have been reported, including Stevens-Johnson syndrome and drug reactions with eosinophilia and systemic symptoms (DRESS), which may be accompanied by liver injury. Probability score: B (Very likely, but rare, a clinically significant cause of liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Information on the use of ethionamide during lactation is scarce. While two infants have been reported to have developmental problems due to ethionamide in their breast milk, their mothers were also exposed to multiple medications during pregnancy and lactation, so these problems are not necessarily attributable to ethionamide. If a mother of an older infant needs to use ethionamide, this is not a reason to stop breastfeeding, but it is best to choose an alternative medication until more data is available, especially when breastfeeding a newborn or premature infant.
◉ Effects on Breastfed Infants
Ethionamide was used as part of a multidrug regimen to treat two pregnant women with multidrug-resistant tuberculosis. One woman used ethionamide throughout her pregnancy and postpartum, while the other used it only postpartum. Both infants were breastfed (the extent and duration of breastfeeding were not specified). Both children were developmentally normal at 4.6 and 5.1 years of age, respectively; one child had mild language delay, and the other had ADHD.
◉ Effects on Lactation and Breast Milk
No relevant published information was found as of the revision date.

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Protein Binding
Approximately 30% is bound to proteins.

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Interactions
Patients taking ethionamide should avoid excessive alcohol consumption, as there have been reports of excessive alcohol consumption leading to psychotic reactions.
Serious serum concentrations of isoniazid may temporarily increase during concomitant treatment with ethionamide.
Ethionamide may enhance the adverse effects of other anti-tuberculosis drugs in the treatment regimen. There is evidence that the adverse effects of ethionamide, cycloserine, and isoniazid on the nervous system may have an additive effect. Seizures have been reported in patients receiving combined treatment with ethionamide and cycloserine; therefore, caution is advised when using these two drugs.
Concomitant use of ethionamide with other neurotoxic drugs may increase the risk of neurotoxicity, such as optic neuritis and peripheral neuritis.
Concomitant use of cycloserine may increase the incidence of central nervous system (CNS) adverse reactions, especially seizures; dose adjustment may be necessary, and close monitoring of patients for CNS toxicity symptoms may be required.

[1]. Vannelli, T.A., A. Dykman, and P.R. Ortiz de Montellano, The antituberculosis drug ethionamide is activated by a flavoprotein monooxygenase. J Biol Chem, 2002. 277(15): p. 12824-9.

[2]. Quemard, A., G. Laneelle, and C. Lacave, Mycolic acid synthesis: a target for ethionamide in mycobacteria? Antimicrob Agents Chemother, 1992. 36(6): p. 1316-21.

Ethionamide may cause developmental toxicity, depending on state or federal labeling requirements. Ethionamide is a yellow crystalline or canary-yellow powder with a mild to moderate sulfurous odor. (NTP, 1992) Ethionamide is a thioformamide, a compound of pyridine-4-thioformamide with an ethyl substituent at the 2-position. It is a prodrug that can be activated by metabolism to the corresponding S-oxide. It is used as an anti-tuberculosis drug, a lipid-lowering drug, a fatty acid synthesis inhibitor, a leprosy treatment drug, and a prodrug. It belongs to the pyridine and thioformamide classes. Ethionamide is a second-line anti-tuberculosis drug that inhibits mycoic acid synthesis. It is also used to treat leprosy. (From Pharmacology Textbook, Smith and Reynard, 1992, p. 868) Ethionamide is an anti-mycobacterial drug. Ethionamide is a second-line drug for tuberculosis treatment, used only in combination with other drugs, and is used to treat drug-resistant tuberculosis. Ethionamide is associated with transient, asymptomatic elevations in serum transaminase levels and, in rare cases, severe acute liver injury. Ethionamide is a nicotinamide derivative with antibacterial activity used to treat tuberculosis. Although the exact mechanism of action of ethionamide is not fully understood, it likely inhibits the synthesis of mycolic acid (a saturated fatty acid found in bacterial cell walls), thereby inhibiting bacterial cell wall synthesis. This ultimately leads to bacterial cell wall rupture and cell lysis. The mechanism of action of ethionamide depends on the drug concentration at the site of infection and the sensitivity of the pathogen, and may manifest as either bacteriostatic or bactericidal effects.
A second-line anti-tuberculosis drug that inhibits mycolic acid synthesis.

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Indications
For the treatment of pulmonary and extrapulmonary tuberculosis unresponsive to other anti-tuberculosis drugs.

FDA Label

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Mechanism of Action
The mechanism of action of ethionamide depends on the drug concentration at the site of infection and the susceptibility of the pathogen, and may manifest as either bacteriostatic or bactericidal action. Ethionamide, like prothionamide and pyrazinamide, is a nicotinic acid derivative and is associated with isoniazid. Ethionamide is thought to undergo intracellular modifications, and its mode of action is similar to that of isoniazid. Isoniazid inhibits the synthesis of mycolic acid, an important component of the bacterial cell wall. Specifically, isoniazid inhibits the enoyl reductase InhA of Mycobacterium tuberculosis by forming a covalent adduct with the NAD cofactor. It is this INH-NAD adduct that acts as a slow, tight competitive inhibitor of InhA. The action of ethionamide may be either bacteriostatic or bactericidal, depending on the drug concentration at the site of infection and the susceptibility of the infecting microorganism. The exact mechanism of action of ethionamide is not fully elucidated, but the drug appears to inhibit peptide synthesis in susceptible microorganisms.

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Therapeutic Use
Antibacterial (Tuberculosis Suppressant)
Ethionamide is indicated for the treatment of tuberculosis, including tuberculous meningitis, in combination with other anti-tuberculosis drugs, particularly in cases where first-line anti-tuberculosis drugs (streptomycin, isoniazid, rifampin, and ethambutol) have failed or cannot be used due to the emergence of toxic or drug-resistant tuberculosis bacteria. Ethionamide is effective only against mycobacteria. /Included on US product label/
Ethionamide is also used in combination with other anti-leprosy drugs to treat leprosy. /Not included on US product label/
Ethionamide is used to treat atypical mycobacterial infections, such as Mycobacterium avium complex (MAC) infections. /Not included on US product label/
Ethionamide and prothionamide are thioamide drugs used as second-line anti-tuberculosis drugs to treat multidrug-resistant tuberculosis.

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Drug Warnings
The most common adverse reactions to ethionamide are gastrointestinal reactions, including nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste in the mouth, stomatitis, anorexia, and weight loss. Nausea and vomiting can be very severe, requiring discontinuation of ethionamide. Gastrointestinal reactions appear to be dose-related, with approximately 50% of patients unable to tolerate a single 1-gram dose.
Psychotic disorders, depression, agitation, somnolence, dizziness, headache, orthostatic hypotension, and weakness have been occasionally reported with ethionamide. In rare cases, peripheral neuritis, paresthesia, seizures, tremor, pellagra-like syndrome, hallucinations, diplopia, optic neuritis, blurred vision, and olfactory dysfunction have been reported.
The manufacturer of ethionamide recommends concurrent administration of pyridoxine to prevent or mitigate neurotoxicity during ethionamide treatment.
Transient increases in serum bilirubin, AST (SGOT), and ALT (SGPT) levels have been reported in patients taking ethionamide. In addition, hepatitis (with or without jaundice) has been reported. Hepatotoxicity is usually reversible after discontinuation of the drug.
For more complete data on drug warnings for ethionamide (22 in total), please visit the HSDB record page.

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Pharmacodynamics
Ethionamide has an inhibitory effect on Mycobacterium tuberculosis. In a study investigating ethionamide resistance, oral administration of ethionamide initially reduced the number of culturable Mycobacterium tuberculosis in the lungs of H37Rv-infected mice. Resistance developed with continued ethionamide monotherapy, but no resistance was observed when mice were treated with ethionamide in combination with streptomycin or isoniazid.

C8H10N2S

166.24

166.056

536-33-4

Ethionamide-d3

2761171

Yellow crystals from ethanol

1.17 g/cm3

167 °C / 1mmHg

164 °C

133.2ºC

1.599

1.978

1

2

2

11

147

0

S=C(C1C([H])=C([H])N=C(C=1[H])C([H])([H])C([H])([H])[H])N([H])[H]

AEOCXXJPGCBFJA-UHFFFAOYSA-N

InChI=1S/C8H10N2S/c1-2-7-5-6(8(9)11)3-4-10-7/h3-5H,2H2,1H3,(H2,9,11)

2-ethylpyridine-4-carbothioamide

Ethioniamide; Trecator; Ethionamide

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)

DMSO : ~250 mg/mL (~1503.85 mM)
H2O : ~0.67 mg/mL (~4.03 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (15.04 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (12.51 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 3: ≥ 2.08 mg/mL (12.51 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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 (Please use freshly prepared in vivo formulations for optimal results.)