Tienilic acid

Tienilic acid
Clinical data
Routes of; administration	Oral
ATC code	C03CC02 (WHO) ;
Legal status
Legal status	Withdrawn;
Pharmacokinetic data
Protein binding	95%
Metabolism	Hepatic
Elimination half-life	6 hours
Excretion	Renal and biliary
Identifiers
	IUPAC name [2,3-dichloro-4-(2-thienylcarbonyl)phenoxy]acetic acid;
CAS Number	40180-04-9;
PubChem CID	38409;
ChemSpider	35204;
UNII	HC95205SY4;
KEGG	D02386;
ChEBI	CHEBI:9590;
ChEMBL	ChEMBL267744;
CompTox Dashboard (EPA)	DTXSID4023670 ;
ECHA InfoCard	100.049.825
Chemical and physical data
Formula	C13H8Cl2O4S
Molar mass	331.16 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES s1cccc1C(=O)c2c(Cl)c(Cl)c(cc2)OCC(=O)O;
	InChI 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-N;

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 It was approved by FDA on May 2, 1979, and withdrawn in 1982, after case reports in the United States indicated a link between the use of ticrynafen and hepatitis.[3]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 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

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.
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. 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.

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[1] 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.

[2] Steele TH (1979). "Mechanism of the uricosuric activity of ticrynafen". Nephron. 23 Suppl 1: 33–7. doi:10.1159/000181665. PMID 471151.

[3] 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.

[4] United States v. SmithKline Beckman et al {BLR 286} Biotechnology Law Report. September–October 1984, 3(9-10): 206-214.

[5] 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.

[6] 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.

[7] 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.