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 It was approved by FDA on May 2, 1979, and withdrawn in 1982, after case reports in the United States indicated a link between the use of ticrynafen and hepatitis.[3]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. However, the metabolic reaction carried out by these enzymes converted tienilic acid to a thiophenesulfoxide which was 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]
Referencesedit
^Schlatter E, Greger R, Weidtke C (March 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". Pflügers Archiv. 396 (3): 210–7. doi:10.1007/bf00587857. PMID 6844125. S2CID 34773678.
^Steele TH (1979). "Mechanism of the uricosuric activity of ticrynafen". Nephron. 23 (Suppl 1): 33–7. doi:10.1159/000181665. PMID 471151.
^Manier JW, Chang WW, Kirchner JP, Beltaos E (June 1982). "Hepatotoxicity associated with ticrynafen--a uricosuric diuretic". The American Journal of Gastroenterology. 77 (6): 401–4. PMID 7091125.
^United States v. SmithKline Beckman et al {BLR 286} Biotechnology Law Report. September–October 1984, 3(9-10): 206-214.
^López-Garcia MP, Dansette PM, Mansuy D (January 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): 166–75. doi:10.1021/bi00167a022. PMID 8286335.
^Beaune P, Dansette PM, Mansuy D, Kiffel L, Finck M, Amar C, et al. (January 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". Proceedings of the National Academy of Sciences of the United States of America. 84 (2): 551–5. Bibcode:1987PNAS...84..551B. doi:10.1073/pnas.84.2.551. PMC304247. PMID 3540968.
^Rademacher PM, Woods CM, Huang Q, Szklarz GD, Nelson SD (April 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. PMC3339269. PMID 22329513.
March 14, 2024
tienilic, acid, ticrynafen, usan, loop, diuretic, drug, with, uric, acid, lowering, uricosuric, action, formerly, marketed, treatment, hypertension, approved, 1979, withdrawn, 1982, after, case, reports, united, states, indicated, link, between, ticrynafen, he. 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 Tienilic acidClinical dataTrade namesSelacrynRoutes ofadministrationOralATC codeC03CC02 WHO Legal statusLegal statusWithdrawnPharmacokinetic dataProtein binding95 MetabolismHepaticElimination half life6 hoursExcretionRenal and biliaryIdentifiersIUPAC name 2 3 dichloro 4 2 thienylcarbonyl phenoxy acetic acidCAS Number40180 04 9PubChem CID38409ChemSpider35204UNIIHC95205SY4KEGGD02386ChEBICHEBI 9590ChEMBLChEMBL267744CompTox Dashboard EPA DTXSID4023670ECHA InfoCard100 049 825Chemical and physical dataFormulaC 13H 8Cl 2O 4SMolar mass331 16 g mol 13D model JSmol Interactive imageSMILES s1cccc1C O c2c Cl c Cl c cc2 OCC O OInChI InChI 1S C13H8Cl2O4S c14 11 7 13 18 9 2 1 5 20 9 3 4 8 12 11 15 19 6 10 16 17 h1 5H 6H2 H 16 17 Key AGHANLSBXUWXTB UHFFFAOYSA NCriminal 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 However the metabolic reaction carried out by these enzymes converted tienilic acid to a thiophene sulfoxide which was 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 Schlatter E Greger R Weidtke C March 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 396 3 210 7 doi 10 1007 bf00587857 PMID 6844125 S2CID 34773678 Steele TH 1979 Mechanism of the uricosuric activity of ticrynafen Nephron 23 Suppl 1 33 7 doi 10 1159 000181665 PMID 471151 Manier JW Chang WW Kirchner JP Beltaos E June 1982 Hepatotoxicity associated with ticrynafen a uricosuric diuretic The American Journal of Gastroenterology 77 6 401 4 PMID 7091125 United States v SmithKline Beckman et al BLR 286 Biotechnology Law Report September October 1984 3 9 10 206 214 Lopez Garcia MP Dansette PM Mansuy D January 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 75 doi 10 1021 bi00167a022 PMID 8286335 Beaune P Dansette PM Mansuy D Kiffel L Finck M Amar C et al January 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 Proceedings of the National Academy of Sciences of the United States of America 84 2 551 5 Bibcode 1987PNAS 84 551B doi 10 1073 pnas 84 2 551 PMC 304247 PMID 3540968 Rademacher PM Woods CM Huang Q Szklarz GD Nelson SD April 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 3339269 PMID 22329513 Retrieved from https en wikipedia org w index php title Tienilic acid amp oldid 1207973330, wikipedia, wiki, book, books, library,
