Tienilic acid

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Tienilic acid
Tienilic acid.svg
Clinical data
Routes of
administration
Oral
ATC code C03CC02 (WHO)
Legal status
Legal status
  • Withdrawn
Pharmacokinetic data
Protein binding 95%
Metabolism Hepatic
Biological half-life 6 hours
Excretion Renal and biliary
Identifiers
Systematic (IUPAC) name: [2,3-dichloro-4-(2-thienylcarbonyl)phenoxy]acetic acid
CAS Number 40180-04-9
PubChem (CID) 38409
ChemSpider 35204
UNII HC95205SY4 YesY
KEGG D02386
ChEBI CHEBI:9590
ChEMBL CHEMBL267744
Chemical and physical data
Formula C13H8Cl2O4S
Molar mass 331.17 g/mol
3D model (Jmol) Interactive image

Tienilic acid (INN and BAN) or ticrynafen (USAN) is a loop diuretic drug with uric acid-lowering (uricosuric) action,[1][2] 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 It was approved by FDA on May 2, 1979, and withdrawn in 1982, after case reports in the United States indicated a link between the use of ticrynafen and hepatitis.[3]

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.[4]

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.[5]

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.[6]

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.[7]

References[edit]

  1. ^ Schlatter, E.; Greger, R.; Weidtke, C. (1983). "Effect of "high ceiling" diuretics on active salt transport in the cortical thick ascending limb of Henle's loop of rabbit kidney. Correlation of chemical structure and inhibitory potency". Pflugers Archiv : European journal of physiology. 396 (3): 210–217. doi:10.1007/bf00587857. PMID 6844125. 
  2. ^ Steele, T. H. (1979). "Mechanism of the uricosuric activity of ticrynafen". Nephron. 23 Suppl 1: 33–37. doi:10.1159/000181665. PMID 471151. 
  3. ^ Manier, J. W.; Chang, W. W.; Kirchner, J. P.; Beltaos, E. (1982). "Hepatotoxicity associated with ticrynafen--a uricosuric diuretic". The American journal of gastroenterology. 77 (6): 401–404. PMID 7091125. 
  4. ^ United States v. SmithKline Beckman et al {BLR 286} Biotechnology Law Report. September–October 1984, 3(9-10): 206-214.
  5. ^ Lopez-Garcia, M.P.; Dansette, P.M; Mansuy, D. (1994). "Thiophene derivatives as new mechanism-based inhibitors of cytochromes P-450: inactivation of yeast-expressed human liver cytochrome P-450 2C9 by tienilic acid.". Biochemistry. 33 (1): 166–175. doi:10.1021/bi00167a022. PMID 8286335. 
  6. ^ Beaune, P.; Dansette, P. M.; Mansuy, D.; Kiffel, L.; Finck, M.; Amar, C.; Leroux, J.P.; Homberg, J.C. (1987). "Human anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug". Proc Natl Acad Sci U S A. 33 (2): 551–555. PMC 304247Freely accessible. PMID 3540968.  line feed character in |title= at position 156 (help)
  7. ^ Rademacher, P. M.; Woods, C. M.; Huang, Q.; Szklarz, G. D.; Nelson, S. D. (2012). "Differential Oxidation of Two Thiophene-Containing Regioisomers to Reactive Metabolites by Cytochrome P450 2C9". Chemical Research in Toxicology. 25 (4): 895–903. doi:10.1021/tx200519d. PMC 3339269Freely accessible. PMID 22329513.