Ethionamide

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Ethionamide
Ethionamide.png
Ethionamide ball-and-stick.png
Systematic (IUPAC) name
2-ethylpyridine-4-carbothioamide
Clinical data
Trade names Trecator (Pfizer)
AHFS/Drugs.com monograph
MedlinePlus a682402
Pregnancy cat.
  • C (US)
Legal status
  • Rx only (US) [1]
Routes oral administration
Pharmacokinetic data
Protein binding Approximately 30% bound to proteins.
Half-life 2 to 3 hours
Identifiers
CAS number 536-33-4 YesY
ATC code J04AD03
PubChem CID 2761171
DrugBank DB00609
ChemSpider 2041901 YesY
UNII OAY8ORS3CQ YesY
KEGG D00591 YesY
ChEBI CHEBI:4885 YesY
ChEMBL CHEMBL1441 YesY
Chemical data
Formula C8H10N2S 
Mol. mass 166.244 g/mol
 YesY (what is this?)  (verify)

Ethionamide (INN; chemical name 2-ethylpyridine-4-carbothioamide) 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]

Chemical synthesis [5][edit]

 Ethionamide synthesis chemme

Physicochemical properties[edit]

Pharmacopoeial properties[edit]

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

Solubility[edit]

Very sparingly soluble in water, ether ; sparingly soluble in methanol, ethanol, propylene glycol ; soluble in hot acetone, dichloroethane ; freely soluble in pyridine.[6]

Basic biology information[edit]

In vitro potency against Mycobacterium tuberculosis[edit]

Minimum inhibitory concentration (MIC) against M.tuberculosis (H37Rv): 0.25 microgram/ml [7]

Spectrum of activity[edit]

Antimicrobial spectrum of ethionamide comprises M. tuberculosis, M. bovis and M. segmatis.[8]

Mechanism of action[edit]

Ethionamide is a prodrug[9] 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][10]

Efficacy in humans[edit]

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.[11]

ADME data[edit]

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.[12]

ETA can be administered with food if tolerance is an issue.[13]

Safety and Tolerability[edit]

Human drug-drug interaction[edit]

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. [14]

Human potential toxicity and adverse reactions[edit]

Ethionamide is structurally similar to methimazole, has been shown to inhibit thyroid hormone synthesis, and was reported to cause hypothyroidism in several TB patients.[15]

References[edit]

  1. ^ Trecator (ethionamide) tablet, film coated (Wyeth Pharmaceuticals Company, a subsidiary of Pfizer Inc.) on DailyMed
  2. ^ a b c "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 MH, Sklaney M (August 2003). "Gatifloxacin and ethionamide as the foundation for therapy of tuberculosis". Antimicrob. Agents Chemother. 47 (8): 2442–4. doi:10.1128/AAC.47.8.2442-2444.2003. PMC 166105. PMID 12878502. 
  5. ^ The Organic Chemistry of Drug Synthesis, Volume 1. Daniel Lednicer, Lester A. Mitscher. ISBN 978-0-471-52141-9, 496 pages, February 1977
  6. ^ Merck Index
  7. ^ Rastogi N, Labrousse V, Goh KS. 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. Curr Microbiol. 1996 Sep;33(3):167-75.
  8. ^ http://link.springer.com/article/10.1007%2Fs002849900095# Current Microbiology September 1996, Volume 33, Issue 3, pp 167-175 DOI: 10.1007/s002849900095
  9. ^ Vannelli TA, Dykman A, Ortiz de Montellano PR (April 2002). "The anti-tuberculosis drug ethionamide is activated by a flavoprotein monooxygenase". J. Biol. Chem. 277 (15): 12824–9. doi:10.1074/jbc.M110751200. PMID 11823459. 
  10. ^ Quémard A, Lanéelle G, Lacave C (June 1992). "Mycolic acid synthesis: a target for ethionamide in mycobacteria?". Antimicrob. Agents Chemother. 36 (6): 1316–21. doi:10.1128/aac.36.6.1316. PMC 190338. PMID 1416831. 
  11. ^ http://apps.who.int/prequal/whopar/whoparproducts/TB133part4v1.pdf
  12. ^ Zhu M, Namdar R, Stambaugh JJ, Starke JR, Bulpitt AE, Berning SE, Peloquin CA. Population pharmacokinetics of ethionamide in patients with tuberculosis. Tuberculosis (Edinb). 2002;82(2-3):91-6. http://www.ncbi.nlm.nih.gov/pubmed/12356460
  13. ^ Barbara Auclair, David E. Nix, Rodney D. Adam, Gordon T. James, and Charles A. Peloquin. Pharmacokinetics of Ethionamide Administered under Fasting Conditions or with Orange Juice, Food, or Antacids. Antimicrob Agents Chemother. 2001 March; 45(3): 810–814. doi:10.1128/AAC.45.3.810-814.2001 PMCID:PMC90379
  14. ^ http://labeling.pfizer.com/showlabeling.aspx?id=473
  15. ^ http://www.nejm.org/doi/pdf/10.1056/NEJM200506303522621

External links[edit]

1. http://livertox.nih.gov/Ethionamide.htm

2. http://www.inchem.org/documents/pims/pharm/ethionam.htm

3. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+7473