Ticrynafen
Encyclopedia
Tienilic acid or ticrynafen (USAN
) 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 It was withdrawn in 1982, shortly after its introduction to the market, after case reports in the United States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
.
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. See United States v. SmithKline Beckman et al {BLR 286} Biotechnology Law Report. September–October 1984, 3(9-10): 206-214.
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.
The above explanation is an 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 stoechiometrically. Progress in proteomics may one day give the answer.
United States Adopted Name
United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association , the United States Pharmacopeial Convention , and the American Pharmacists...
) is a diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
drug with uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
-lowering (uricosuric) action, formerly marketed for the treatment of hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
. It was withdrawn in 1982, shortly after its introduction to the market, after case reports in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
indicated a link between the use of ticrynafen and hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
.
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. See United States v. SmithKline Beckman et al {BLR 286} Biotechnology Law Report. September–October 1984, 3(9-10): 206-214.
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
Thiophene
Thiophene is a heterocyclic compound with the formula C4H4S. Consisting of a flat five-membered ring, it is aromatic as indicated by its extensive substitution reactions. Related to thiophene are benzothiophene and dibenzothiophene, containing the thiophene ring fused with one and two benzene...
sulfoxide
Sulfoxide
A sulfoxide is a chemical compound containing a sulfinyl functional group attached to two carbon atoms. Sulfoxides can be considered as oxidized sulfides...
which proved highly electrophilic. This encouraged a Michael reaction
Michael reaction
The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an alpha, beta unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C-C bonds...
leading to alkylation of a thiol
Thiol
In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...
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.
The above explanation is an 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 stoechiometrically. Progress in proteomics may one day give the answer.