Absorption, Distribution and Excretion
Essentially completely absorbed following oral administration and not subjected to any appreciable first pass metabolism. Bioavailability approximately 100%.
Less than 1% of the oral dose is excreted as ethionamide in urine. Ethionamide is extensively metabolized to active and inactive metabolites.
93.5 L [healthy volunteers]
Rapidly absorbed from the gastrointestinal tract following oral administration. Bioavailability approximately 100%.
Ethionamide is essentially completely absorbed following oral administration and does not undergo any appreciable first-pass metabolism.
Following a single 250-mg oral dose of ethionamide given as film-coated tablets in fasting adults, peak plasma concentrations of ethionamide average 2.16 mcg/mL and are attained within 1 hour. When a single 250-mg oral dose of ethionamide is given as sugar-coated tablets (Trecator-SC; no longer commercially available in the US) in healthy adults, peak plasma concentrations average 1.48 mcg/mL and are attained within 1.5 hours.
Time to peak concentration: Approximately 1.8 hours; Peak serum concentration: Approximately 2.2 mcg/mL after a single oral 500-mg dose.
For more Absorption, Distribution and Excretion (Complete) data for ETHIONAMIDE (11 total), please visit the HSDB record page.

---

Metabolism / Metabolites
Hepatic and extensive. Metabolized to the active metabolite sulfoxide, and several inactive metabolites. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis.
Ethionamide is extensively metabolized to active and inactive metabolites. Metabolism is presumed to occur in the liver and thus far 6 metabolites have been isolated: 2-ethylisonicotinamide, carbonyl-dihydropyridine, thiocarbonyl-dihydropyridine, S-oxocarbamoyl dihydropyridine, 2-ethylthioiso-nicotinamide, and ethionamide sulphoxide. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis .

---

Biological Half-Life
2 to 3 hours
The plasma half-life of ethionamide following a 250-mg oral dose given as film-coated tablets is 1.92 hours.
Half-life: Approximately 2 to 3 hours.

Toxicity Summary
IDENTIFICATION: Ethionamide is a drug for the treatment of tuberculosis. Ethionamide is a yellow crystalline powder. Soluble in 1 in 30 of alcohol. Very sparingly soluble in water. Slightly soluble in chloroform. Slightly soluble in ether. Soluble in methyl alcohol. Sparingly soluble in propylene glycol. Indications: For the treatment of pulmonary and extrapulmonary tuberculosis in conjunction with other antituberculous agents (when resistance to primary agents has developed). For the treatment of leprosy, as part of multi-drug regimens. In the treatment of pulmonary disease in Mycobacterium kansasii and other atypical mycobacteria. HUMAN EXPOSURE: Main risks and target organs: Most common adverse reactions are gastrointestinal disturbances including anorexia, nausea, vomiting, excessive salivation, a metallic taste, stomatitis and diarrhoea and hepatitis. Central nervous system effects include dizziness, drowsiness, headaches, convulsions, peripheral neuropathy, tremors and paraesthesias. There is no experience in acute overdose of ethionamide. One of the metabolites resembles isoniazid and one should watch for similar symptoms. Summary of clinical effects: Gastrointestinal: Anorexia, vomiting, stomatitis, diarrhea, System: excessive salivation, metallic taste, hepatotoxicity. Central Nervous: Mental depression, anxiety or psychosis, System: encephalopathy with pellagra-like symptoms, dizziness, drowsiness, headache, convulsion, peripheral neuropathy, tremors, paresthesias. Eye: Optic neuritis, optic atrophy, diplopia. Nose: olfactory disturbances Ear: Deafness Endocrine: Hypothyroidism, gynecomastia, impotence, menorrhagia, hypoglycemia. Integumentary: Alopecia, acne, severe allergic rashes, photodermatitis. Hematology: Thrombocytopenia Skeletal system: Rheumatic pains Cardiovascular: Postural hypotension Contraindications: Ethionamide should not be given to pregnant women unless the benefits outweigh its possible risk. To be used with caution in women of child-bearing age. Individuals with severe liver disease. Severe hypersensitivity. Note: Caution is necessary in administering ethionamide to patients with depression or other psychiatric diseases, chronic alcoholism, epilepsy, hypothyroidism or diabetes mellitus. Routes of entry: Oral: This is the usual route of administration for therapeutic use. Parenteral: Ethionamide hydrochloride has been given intravenously, but there is no commercial preparation. Other: Ethionamide has been administered as rectal suppositories. Absorption by route of exposure: Approximately 80% of a gastrointestinal oral dose of ethionamide is rapidly absorbed from the gastrointestinal tract. After oral administration, the bioavailability is about 100%. Relative bioavailability after rectal administration was 57.3% of that following oral administration. Distribution by route of exposure: It is widely distributed throughout body tissues and fluids. It crosses the placenta and penetrates the meninges, appearing in the CSF in concentrations equivalent to those in the serum. Protein binding is low (10%). Biological half-life by route of exposure: Half-life is 2 to 3 hours. Ethionamide is extensively metabolized, probably in the liver, to ethionamide sulfoxide, 2-ethylisonicotinic acid and 2-ethylisonicotinamide. The sulfoxide is the main active metabolite. Elimination by route of exposure: Less than 1% of a dose appears in the urine as unchanged drug, the remainder is excreted in the urine as inactive metabolites. Mode of action: Toxicodynamics: In view of the structural similarity of the metabolite 2-methylisonicotinic acid to isoniazid, it has been suggested that toxicity is due to pyridoxine deficiency. Pharmacodynamics: Ethionamide inhibits the synthesis of mycolic acids and stimulates oxidation reduction reactions. Treated cells lose acid fastness. Both the drug and the sulfoxide metabolite are active against M.tuberculosis. 2-ethylisonicotinic acid and 2-ethylisonicotinamide are not active metabolites. It is bacteriostatic against M. tuberculosis at therapeutic concentrations, but may be bactericidal at higher concentrations. It is bactericidal against M. lepra. Resistance develops rapidly if used alone and there is complete cross-resistance with prothionamide, thiacetazone and thiambutosine. Toxicity: Adults: In clinical use, neuropsychiatric symptoms, such as headache, sleeping, insomnia, depression and paresthesia may occur. Elevation of liver transaminase enzymes has been known to develop. No special precautions are required due to age, as doses are adjusted according to patient response. However, dose should be modified depending on liver and renal status. Interactions: Ethionamide taken with pyrazinamide may lead to abnormalities of liver function and the use of these two agents together should be avoided. The use of rifampicin with the thioamides (ethionamide or prothionamide) as part of the treatment of multibacillary leprosy has been associated with an unexpectedly high incidence of hepatotoxicity. Adverse nervous system effects of ethionamide, cylcoserine and isoniazid may be additive. The side effects of other tuberculostatic agents may be enhanced when ethionamide is administered concomitantly. Alcohol may contribute to psychotropic reactions in an ethionamide treated patient. More study is needed to clarify the clinical significance of this interaction. Main adverse effects: The most common adverse effects are dose-related, viz: gastrointestinal disturbances, including anorexia, excessive salivation, a metallic taste, nausea, vomiting, stomatitis, diarrhea and hepatitis. Dizziness, drowsiness, headache, postural hypotension and asthenia may also occur occasionally. Other side effects reported include acne, allergic reactions alopecia, convulsions, deafness, dermatitis (including photodermatitis), visual disturbances, tremors, gynecomastia, impotence, menstrual disturbances, olfactory disorders, peripheral and optic neuropathy, thrombocytopenia and rheumatic pains. Mental disturbances, including depression, anxiety and psychosis have been provoked. A pellagra-like syndrome with encephalopathy has been reported rarely. A tendency towards hypoglycemia may occur and could be of significance in patients with diabetes mellitus. Hypothyroidism has also occurred. Racial differences in tolerance may occur, e.g. Chinese and Africans are often more tolerant of ethionamide than are Europeans. ANIMAL/PLANT STUDIES: A rat study showed the sublethal neurotoxicity which included paralysis, loss of screen grip and decreased motor activity. Teratogenicity: Teratogenic effects have been reported in rabbits, mice and rats, in which high doses have led to abortions and some malformations. Mutagenicity: Ethionamide was not found to be mutagenic as shown by Ames Salmonella and micronuclei assay test.

---

Hepatotoxicity
Ethionamide therapy has been linked to elevations in serum aminotransferase levels in a proportion of patients, but these elevations are typically self-limited and asymptomatic. More importantly, ethionamide has been linked to many instances of clinical apparent acute liver injury that arise in up to 5% of patients and can be severe and even fatal. The time to onset and clinical features of hepatic injury due to ethionamide resemble those of isoniazid, the latency ranging from 2 weeks to more than 6 months after starting (most arise within 1 to 3 months), and the pattern of enzyme elevations typically being hepatocellular and resembling acute viral hepatitis. Features of hypersensitivity (rash, fever and eosinophilia) are uncommon. Like isoniazid, ethionamide therapy may be associated with development of autoantibodies (typically ANA), but titers are generally low and rarely accompanied by autoimmune conditions. Cases of severe hypersensitivity reaction including Stevens Johnson Syndrome and DRESS which can be accompanied by liver injury have been described with ethionamide.
Likelihood score: B (highly likely although rare cause of clinically apparent liver injury).

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Minimal information exists on the use of ethionamide during breastfeeding. Although some developmental problems have been reported in two infants exposed to ethionamide in breastmilk, their mothers were also exposed to several drugs during pregnancy and during breastfeeding, so the problems cannot necessarily be attributed to ethionamide. If ethionamide is required by the mother of an older infant, it is not a reason to discontinue breastfeeding, but until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Ethionamide was used as part of multidrug regimens to treat two pregnant women with multidrug-resistant tuberculosis, one throughout pregnancy and postpartum and the other postpartum only. The infants were breastfed (extent and duration not stated). At age 4.6 and 5.1 years, the children were developing normally except for a mild speech delay in one and hyperactivity in the other.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

---

Protein Binding
Approximately 30% bound to proteins.

---

Interactions
Patients receiving ethionamide should avoid excessive ingestion of alcohol because a psychotic reaction has been reported in this situation.
Serum concentrations of isoniazid may increase temporarily during concomitant ethionamide therapy.
Ethionamide may potentiate the adverse effects of other antituberculosis agents included in the treatment regimen. There is some evidence that adverse nervous system effects of ethionamide, cycloserine, and isoniazide may be additive. Seizures have been reported in patients receiving regimens that included both ethionamide and cycloserine and caution is advised if these drugs are used concomitantly.
Concurrent administration of ethionamide with other neurotoxic medications may increase the potential for neurotoxicity, such as optic and peripheral neuritis.
Concurrent use /of cycloserine/ may result in increased incidence of central nervous system [CNS] effects, especially seizures; dosage adjustments may be necessary and patients should be monitored closely for signs of CNS toxicity.

[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 can cause developmental toxicity according to state or federal government labeling requirements.
Ethionamide appears as yellow crystals or canary yellow powder with a faint to moderate sulfide odor. (NTP, 1992)
Ethionamide is a thiocarboxamide that is pyridine-4-carbothioamide substituted by an ethyl group at position 2. A prodrug that undergoes metabolic activation by conversion to the corresponding S-oxide. It has a role as an antitubercular agent, an antilipemic drug, a fatty acid synthesis inhibitor, a leprostatic drug and a prodrug. It is a member of pyridines and a thiocarboxamide.
A second-line antitubercular agent that inhibits mycolic acid synthesis. It also may be used for treatment of leprosy. (From Smith and Reynard, Textbook of Pharmacology, 1992, p868)
Ethionamide is an Antimycobacterial.
Ethionamide is a second line drug in the therapy of tuberculosis used only in combination with other agents and for drug-resistant tuberculosis. Ethionamide has been linked to transient, asymptomatic elevations in serum aminotransferase levels and in uncommon instances of acute liver injury, which can be severe.
Ethionamide is a nicotinamide derivative, with antibacterial activity, used to treat tuberculosis. Although the exact mechanism of action of ethionamide is unknown, it may inhibit the synthesis of mycolic acid, a saturated fatty acid found in the bacterial cell wall, thereby inhibiting bacterial cell wall synthesis. This eventually leads to bacterial cell wall disruption and cell lysis. Ethionamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug at the site of infection and the susceptibility of the organism involved.
A second-line antitubercular agent that inhibits mycolic acid synthesis.

---

Drug Indication
For use in the treatment of pulmonary and extrapulmonary tuberculosis when other antitubercular drugs have failed.
FDA Label

---

Mechanism of Action
Ethionamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. Ethionamide, like prothionamide and pyrazinamide, is a nicotinic acid derivative related to isoniazid. It is thought that ethionamide undergoes intracellular modification and acts in a similar fashion to isoniazid. Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. Specifically isoniazid inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA.
Ethionamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. The exact mechanism of action of ethionamide has not been fully elucidated, but the drug appears to inhibit peptide synthesis in susceptible organisms.

---

Therapeutic Uses
Antibacterial (tuberculostatic)
Ethionamide is indicated in combination with other antituberculosis medications in the treatment of tuberculosis, including tuberculous meningitis, after failure with the primary medications (streptomycin, isoniazid, rifampin, and ethambutol) or when these cannot be used because of toxicity or development of resistant tubercle bacilli. Ethionamide is effective only against mycobacteria. /Included in US product label/
Ethionamide is used in combination with other antileprosy agents in the treatment of Hansen's disease. /Not included in US product label/
Ethionamide is used in the treatment of atypical mycobacterial infections, such as Mycobacterium avium complex (MAC). /Not included in US product label/
Ethionamide and prothionamide are thioamides used as second-line antituberculosis drugs for treatment of multi-drug resistant tuberculosis.

---

Drug Warnings
Adverse GI effects, including nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia, and weight loss, are the most common adverse effects reported with ethionamide. Nausea and vomiting may be severe enough to necessitate discontinuance of ethionamide. GI effects appear to be dose related, and approximately 50% of patients are unable to tolerate a single 1-g dose of the drug.
Psychotic disturbances, mental depression, restlessness, drowsiness, dizziness, headache, postural hypotension, and asthenia occur occasionally with ethionamide. Rarely, peripheral neuritis, paresthesia, seizures, tremors, a pellagra-like syndrome, hallucinations, diplopia, optic neuritis, blurred vision, and olfactory disturbances have been reported.
The manufacturer of ethionamide recommends concomitant use of pyridoxine to prevent or relieve neurotoxic effects during ethionamide treatment.
Transient increases in serum bilirubin, AST (SGOT), and ALT (SGPT) concentrations have been reported in patients receiving ethionamide. Hepatitis (with or without jaundice) also has been reported. Hepatotoxicity generally is reversible following discontinuance of the drug.
For more Drug Warnings (Complete) data for ETHIONAMIDE (22 total), please visit the HSDB record page.

---

Pharmacodynamics
Ethinamate is bacteriostatic against M. tuberculosis. In a study examining ethionamide resistance, ethionamide administered orally initially decreased the number of culturable Mycobacterium tuberculosis organisms from the lungs of H37Rv infected mice. Drug resistance developed with continued ethionamide monotherapy, but did not occur when mice received 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.

---

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.

---

View More

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.

---

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