Ticrynafen
Ticrynafen, or tienilic acid, is a diuretic drug with uric acid-lowering (uricosuric) action, formerly marketed for the treatment of hypertension. It was withdrawn in 1982, shortly after its introduction to the market, after case reports in the United States indicated a link between the use of ticrynafen and hepatitis. (Manier et al., 1982)
the diuretic agent tienilic acid had to be withdrawn from the market because it was found to act as a suicide substrate at the cytochrome P450 enzymes involved in drug metabolism.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 sulphoxide 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 sulphoxide restored the thiophene ring and resulted in tienilic acid being covalently linked to the enzyme, thus inhibiting the enzyme irreversibly.
References
- Manier JW, Chang WW, Kirchner JP, Beltaos E (1982). Hepatotoxicity associated with ticrynafen – a uricosuric diuretic. Am J Gastroenterol 77 (6), 401-4. PMID 7091125