Tienilic acid

C4H7CIO2 105-39-5) see Azimilide hydrochloride Cloricromen Etomidate Ibuprofen Piracetam Retinol Tiaramide Tienilic acid ethyl 2-chloroacctoacetate... 

C5H3CIOS 5271-67-0) see Stepronin Suprofen Tenonitrozole Tienilic acid 2-(2-then6ylthio)propionic acid (CjHg03S2 81466-67-3) see Stepronin... 

C4H4S 110-02-1). see Clopidogrel hydrogensulfate Oxitefonium bromide Penthienate methobromide Suprofen 2-Thiophenecarboxylic acid Tiaprofenic acid Ticlopidine Tiemonium iodide Tienilic acid... 

Tienilic acid- and dihydralazine-induced hepatitis are associated with antibodies against Cyp 2C9 [53] and Cyp 1A2 [54, 55], respectively. These are also the same cytochrome P450s that are responsible for the formation of reactive metabolites of these two drags. Anticonvulsant hepatotoxicity is associated with antibodies against rodent Cyp 3 A and related human enzymes such as thromboxane synthase [56, 57], It is interesting to note that cytochromes P450 are often the target of autoantibodies in idiopathic autoimmune hepatitis [58],... 

Lecoeur, S., Andre, C., and Beaune, P.H., Tienilic acid-induced autoimmune hepatitis Antiliver and-kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9, Mol. Pharmacol., 50,326, 1996. 

Koenigs LL, Peter RM, Hunter AP, et al. Electrospray ionization mass spectrometric analysis of intact cytochrome P450 identification of tienilic acid adducts to P450 2C9. Biochemistry 1999 38(8) 2312 2319. 

There are several examples of autoimmune hepatitis caused by mechanism-based inhibitors in the field of CYPs hepatitis induced by halothane (CYP2E1) [15,16], by tienilic acid (CYP2C9) [17] and by dihydralazine (CYP1A2) [18,19]. 

In the case of tienilic acid induced hepatitis, Beaune et al. [20] have shown that autoantibodies against CYP2C9 are present in the serum of patients suffering from the disease. Additional in vitro evidence has shown the potential for tienilic acid to alkylate CYP2C9 [21]. 

Fig. 8.23 Structure of tienilic acid (A) and an isomeric variant (B) which cause hepatotoxicity by autoimmune and direct mechanisms respectively, following conversion to sulphoxide metabolites and resultant electrophilic carbon atoms.

When clearance is dependent upon metabolism, species-specific differences in the enzymes of metabolism can clearly prevent any such allometric relationship. An example of this is the absence of a close homologue of the human CYP2C9 enzyme in the dog, hence its inability to hydroxylate drugs such as tolbutamide and tienilic acid [13]. This said, many compounds cleared by metabolism do exhibit allometric relationships (e.g. N-nitrosodimethylamine, [14]). In an extensive analysis of the allometric relationship between clearance in the rat and man for 54 extensively cleared... 

Major drugs withdrawn between 1971 and 1982 for safety reasons included polidexide (introduced 1974 and withdrawn 1975), oral formulation of practolol (1970 and 1976), alclofenac (1972 and 1979), tienilic acid (1979 and 1980), clomacron (1977 and 1982) and indoprofen (1982 and 1982). 

B Non-planar lipophilic molecules usually with V-shaped geometries Phenobarbital Secobarbital Phenobarbital Tienilic acid... 

Mancy, A., Broto, P., Dijols, S., Dansette, P. M., and Mansuy, D. (1995) The substrate binding site of human liver cytochrome P450 2C9 an approach using designed tienilic acid derivatives and molecular modeling. Biochemistry 34, 10,365-10,375. 

C9 Celecoxib, flurbiprofen, hexobarbital, ibuprofen, losartan, phenytoin, tolbutamide, trimethadione, sulfaphenazole, S-warfarin, ticrynafen Barbiturates, rifampin Tienilic acid, sulfaphenazole... 

C9 Tienilic acid, tolbutamide, warfarin, phenytoin, THC, hexobarbital, diclofenac [Diclofenac (4 -OH)]... 

In the field of hypertension, despite the unfortunate and unexpected adverse effects of practolol, tienilic acid, and mibefradil, it has been generally considered that fall in blood pressure was an acceptable sur-... 

Metabolism-dependent conversion of the drug candidate to a metabolite that quasi-irreversibly coordinates with the heme iron (e.g., troleando-mycin) or irreversibly (covalently) binds to amino acid residues or the heme moiety of a CYP enzyme in such a way as to completely prevent or significantly diminish catalytic activity (e.g., tienilic acid). 

Melet A, Assrir N, Jean P, et al. Substrate selectivity of human cytochrome P450 2C9 importance of residues 476, 365, and 114 in recognition of diclofenac and sulfaphenazole and in mechanism-based inactivation by tienilic acid. Arch Biochem Biophys 2003 409 80-91. 

Lopez-Garcia MP, Dansette PM, Mansuy D. 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 1994 33 166-175. 

Robin MA, Maratrat M, Le Roy M, et al. Antigenic targets in tienilic acid hepatitis. Both cytochrome P450 2C11 and 2Cll-tienilic acid adducts are transported to the plasma membrane of rat hepatocytes and recognized by human sera. J Clin Invest 1996 98 1471-1480. 

Examples of xenobiotics that bind to proteins and fall into this class of mechanism-based inhibitor include tienilic acid, cannabidiol, chloramphenicol, secobarbital, some psoralens, spironolactone, mifepristone, and grapefruit juice. 

Chloramphenicol and secobarbital exhibit properties similar to those of tienilic acid, but they have not been studied in humans (11). Oxidative dechlorination of chloramphenicol with formation of reactive acyl chlorides appears to be an important metabolic pathway for irreversible inhibition of CYP. Chloramphenicol binds to CYP, and subsequent substrate hydroxylation and product release are not impaired. The inhibition of CYP oxidation and the inhibition of endogenous NADPH oxidase activity suggest that some modification of the CYP has taken place, which inhibits its ability to accept electrons from the CYP reductase (11). Secobarbital completely inactivates rat CYP2B1 functionally, with partial loss of the heme chromophore. Isolation of the N-alkylated secobarbital heme adduct and the modified CYP2B1 protein revealed that the metabolite partitioned between heme N-alkylation, CYP2B1 protein modification, and epoxidation. A small fraction of the prosthetic heme modifies the protein and contributes to the CYP2B1 inactivation (12). 

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