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- Q7801054 subject Q6811985.
- Q7801054 subject Q7145095.
- Q7801054 subject Q8385000.
- Q7801054 subject Q8852392.
- Q7801054 subject Q8919936.
- Q7801054 subject Q8965786.
- Q7801054 abstract "Tienilic acid (INN and BAN) or ticrynafen (USAN) is a loop diuretic drug with uric acid-lowering (uricosuric) action, formerly marketed for the treatment of hypertension. It was approved by FDA on May 2, 1979, and withdrawn in 1982, after case reports in the United States indicated a link between the use of ticrynafen and hepatitis.Criminal charges were brought against SmithKline executives with regard to hiding data related to toxicity while gaining FDA approval. The company pleaded guilty to 14 counts of failure to report adverse reactions and 20 counts of selling a misbranded drug.Tienilic acid was found to act as a suicide substrate at the cytochrome P450 enzymes involved in drug metabolism. Unfortunately, the metabolic reaction carried out by these enzymes converted tienilic acid to a thiophene sulfoxide which proved highly electrophilic. This encouraged a Michael reaction leading to alkylation of a thiol group in the enzyme's active site. Loss of water from the thiophene sulfoxide restored the thiophene ring and resulted in tienilic acid being covalently linked to the enzyme, thus inhibiting the enzyme irreversibly.In addition sera of patients who had liver failure after taking this drug contained antibodies recognizing CYP2C9 able to hydroxylate the drug and to give covalent binding.The above explanation is a hypothesis. It is still not known (after 15 years) if the reactive intermediate which inactivates the CYP2C9 is the thiophene sulfoxide or the thiophene epoxide. The target on the protein is also not known (could be multiple). However tienilic acid is a good mechanism based inhibitor of CYP2C9 and seems to inactivate it stoichiometrically. Progress in proteomics may one day give the answer.Recent studies indicate that in fact the primary metabolite of tienilic acid (5-OH tienilic acid) cannot be derived from a thiophene-S-oxide intermediate as was previously hypothesized. It was determined to be derived from a thiophene epoxide intermediate and this reactive intermediate is then likely a cause for the covalent binding to as well as mechanism-based inactivation of CYP2C9.".
- Q7801054 atcPrefix "C03".
- Q7801054 atcSuffix "CC02".
- Q7801054 casNumber "40180-04-9".
- Q7801054 chEBI "9590".
- Q7801054 fdaUniiCode "HC95205SY4".
- Q7801054 iupacName "[2,3-dichloro-4-(2-thienylcarbonyl)phenoxy]acetic acid".
- Q7801054 pubchem "38409".
- Q7801054 thumbnail Tienilic_acid.svg?width=300.
- Q7801054 wikiPageWikiLink Q105522.
- Q7801054 wikiPageWikiLink Q131742.
- Q7801054 wikiPageWikiLink Q220410.
- Q7801054 wikiPageWikiLink Q30.
- Q7801054 wikiPageWikiLink Q305364.
- Q7801054 wikiPageWikiLink Q407693.
- Q7801054 wikiPageWikiLink Q408395.
- Q7801054 wikiPageWikiLink Q41861.
- Q7801054 wikiPageWikiLink Q424280.
- Q7801054 wikiPageWikiLink Q4926095.
- Q7801054 wikiPageWikiLink Q642233.
- Q7801054 wikiPageWikiLink Q6811985.
- Q7801054 wikiPageWikiLink Q7145095.
- Q7801054 wikiPageWikiLink Q7544891.
- Q7801054 wikiPageWikiLink Q824258.
- Q7801054 wikiPageWikiLink Q8385000.
- Q7801054 wikiPageWikiLink Q8852392.
- Q7801054 wikiPageWikiLink Q8919936.
- Q7801054 wikiPageWikiLink Q8965786.
- Q7801054 wikiPageWikiLink Q908086.
- Q7801054 wikiPageWikiLink Q918753.
- Q7801054 wikiPageWikiLink Q9368.
- Q7801054 wikiPageWikiLink Q9377.
- Q7801054 atcPrefix "3.0".
- Q7801054 atcSuffix "CC02".
- Q7801054 casNumber "40180".
- Q7801054 chebi "9590".
- Q7801054 iupacName "[2,3-dichloro-4-phenoxy]acetic acid".
- Q7801054 pubchem "38409".
- Q7801054 unii "HC95205SY4".
- Q7801054 type ChemicalSubstance.
- Q7801054 type Drug.
- Q7801054 type ChemicalObject.
- Q7801054 type Thing.
- Q7801054 type Q8386.
- Q7801054 comment "Tienilic acid (INN and BAN) or ticrynafen (USAN) is a loop diuretic drug with uric acid-lowering (uricosuric) action, formerly marketed for the treatment of hypertension. It was approved by FDA on May 2, 1979, and withdrawn in 1982, after case reports in the United States indicated a link between the use of ticrynafen and hepatitis.Criminal charges were brought against SmithKline executives with regard to hiding data related to toxicity while gaining FDA approval.".
- Q7801054 label "Tienilic acid".
- Q7801054 depiction Tienilic_acid.svg.