Ethionamide

Ethionamide
Clinical data
Trade names Trecator
AHFS/Drugs.com Monograph
MedlinePlus a682402
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 By mouth
ATC code J04AD03 (WHO)
Legal status
Legal status
  • US: Rx-only[1]
Pharmacokinetic data
Protein binding ~30%
Biological half-life 2 to 3 hours
Identifiers
CAS Number 536-33-4 YesY
PubChem (CID) 2761171
DrugBank DB00609 YesY
ChemSpider 2041901 YesY
UNII OAY8ORS3CQ YesY
KEGG D00591 YesY
ChEBI CHEBI:4885 YesY
ChEMBL CHEMBL1441 YesY
ECHA InfoCard 100.007.846
Chemical and physical data
Formula C8H10N2S
Molar mass 166.244 g/mol
3D model (Jmol) Interactive image
  (verify)

Ethionamide (INN) is an antibiotic used in the treatment of tuberculosis. It was discovered in 1956.[2] It is sold under the brand name Trecator or Trecator SC [3] by Wyeth Pharmaceuticals which was purchased by Pfizer in 2009.

Ethionamide is part of a group of drugs used in the treatment of drug resistant TB called thioamides. It is used as part of treatment regimens, generally involving 5 medicines, to treat MDR and XDR TB.[2] Ethionamide is used as part of a South Africa’s standard regimen to treat MDR TB. It has been proposed for use in combination with gatifloxacin.[4]

It is on the World Health Organization's List of Essential Medicines, the most important medications need in a basic health system.[5]

Medical uses

Minimum inhibitory concentration (MIC) against M. tuberculosis (H37Rv): 0.25 microgram/ml.[6]

Efficacy

Ethionamide is indicated in combination with other antituberculosis agents for the treatment of all forms of tuberculosis caused by Mycobacterium tuberculosis. However, ethionamide is only indicated as a second-line antimycobacterial drug when resistance to or toxicity from first-line drugs has developed.[7]

Ethionamide (ETA) pharmacokinetic parameters differed between TB patients and healthy volunteers, possibly due to differences in the completeness of absorption. Doses of at least 500 mg appear to be required to achieve serum concentrations above the typical ETA MIC.[8]

ETA can be administered with food if tolerance is an issue.[9]

Spectrum of activity

Antimicrobial spectrum of ethionamide comprises M. tuberculosis, M. bovis and M. segmatis.[6]

Adverse effects

Ethionamide is structurally similar to methimazole, has been shown to inhibit thyroid hormone synthesis, and was reported to cause hypothyroidism in several TB patients.[10]

Interaction

Trecator has been found to temporarily raise serum concentrations of isoniazid. Trecator may potentiate the adverse effects of other antituberculous drugs administered concomitantly. In particular, convulsions have been reported when ethionamide is administered with cycloserine and special care should be taken when the treatment regimen includes both of these drugs. Excessive ethanol ingestion should be avoided because a psychotic reaction has been reported.[11]

Mechanism of action

Ethionamide is a prodrug[12] It is activated by the enzyme EthA, a mono-oxygenase in Mycobacterium tuberculosis, and binds NAD+ to form an adduct which inhibits InhA in the same way as isoniazid. Expression of the ethA gene is controlled by EthR, a transcriptional repressor. It is understood that improving ethA expression will increase the efficacy of ethionamide and so EthR inhibitors are of great interest to co-drug developers. The action may be through disruption of mycolic acid.[2][13]

Physicochemical properties

Pharmacopoeial properties

Ethionamide was described in an official monograph in several pharmacopoeia, e.g.The International Pharmacopoeia, USP and Ph.Eur.

Solubility

Very sparingly soluble in water, ether; sparingly soluble in methanol, ethanol, propylene glycol; soluble in hot acetone, dichloroethane; freely soluble in pyridine.[14]

Synonyms

References

  1. ↑ Trecator (ethionamide) tablet, film coated (Wyeth Pharmaceuticals Company, a subsidiary of Pfizer Inc.) on DailyMed
  2. 1 2 3 "Ethionamide". TB Online. Global Tuberculosis Community Advisory Board. Retrieved 2012-08-18.
  3. ↑ "Trecator and Trecator SC tablet by Wyeth" |http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM164879.pdf
  4. ↑ Cynamon, M. H.; Sklaney, M. (2003). "Gatifloxacin and Ethionamide as the Foundation for Therapy of Tuberculosis". Antimicrobial Agents and Chemotherapy. 47 (8): 2442–4. doi:10.1128/AAC.47.8.2442-2444.2003. PMC 166105Freely accessible. PMID 12878502.
  5. ↑ "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 2 February 2015.
  6. 1 2 Rastogi, Nalin; Labrousse, Valérie; Goh, Khye Seng (1996). "In Vitro Activities of Fourteen Antimicrobial Agents Against Drug Susceptible and Resistant Clinical Isolates of Mycobacterium tuberculosis and Comparative Intracellular Activities Against the Virulent H37Rv Strain in Human Macrophages". Current Microbiology. 33 (3): 167–75. doi:10.1007/s002849900095. PMID 8672093.
  7. ↑ http://apps.who.int/prequal/whopar/whoparproducts/TB133part4v1.pdf[]
  8. ↑ Zhu, M.; Namdar, R.; Stambaugh, J.J.; Starke, J.R.; Bulpitt, A.E.; Berning, S.E.; Peloquin, C.A. (2002). "Population pharmacokinetics of ethionamide in patients with tuberculosis". Tuberculosis. 82 (2–3): 91–6. doi:10.1054/tube.2002.0330. PMID 12356460.
  9. ↑ Auclair, B.; Nix, D. E.; Adam, R. D.; James, G. T.; Peloquin, C. A. (2001). "Pharmacokinetics of Ethionamide Administered under Fasting Conditions or with Orange Juice, Food, or Antacids". Antimicrobial Agents and Chemotherapy. 45 (3): 810–4. doi:10.1128/AAC.45.3.810-814.2001. PMC 90379Freely accessible. PMID 11181366.
  10. ↑ McDonnell, Marie E.; Braverman, Lewis E.; Bernardo, John (2005). "Hypothyroidism Due to Ethionamide". New England Journal of Medicine. 352 (26): 2757–9. doi:10.1056/NEJM200506303522621. PMID 15987931.
  11. ↑ http://labeling.pfizer.com/showlabeling.aspx?id=473[]
  12. ↑ Vannelli, T. A.; Dykman, A.; Ortiz De Montellano, P. R. (2002). "The Antituberculosis Drug Ethionamide is Activated by a Flavoprotein Monooxygenase". Journal of Biological Chemistry. 277 (15): 12824–9. doi:10.1074/jbc.M110751200. PMID 11823459.
  13. ↑ Quemard, A; Laneelle, G; Lacave, C (1992). "Mycolic acid synthesis: A target for ethionamide in mycobacteria?". Antimicrobial Agents and Chemotherapy. 36 (6): 1316–21. doi:10.1128/aac.36.6.1316. PMC 190338Freely accessible. PMID 1416831.
  14. ↑ Merck Index
  15. ↑ Somner, A.R. (1959). "2-Ethylisothionicotinamide ('1314') in pulmonary tuberculosis: A controlled trial of drug tolerance". Tubercle. 40 (6): 457–461. PMID 13832783.
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