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Influence of non-steroid anti=inflammatory drugs (NSAIDd) on hepatic tyrosine aminotransferase (TA) activity in rats in vitro and in vivo.
Authors:C Reinicke
Institution:Institute of Pharmacology and Toxicology, Friedrich Schiller University, Jena, GDR
Abstract:Indomethacin, flufenamic acid, mefenamic acid, gold sodium thiosulphate and ibuprofen were found to be inhibitors of hepatic TA in vitro. The type of inhibition was competitive relative to l-tyrosine; apparent Ki values ranged from 0.7 × 10?4 to 1.18 × 10?3 M. Several other NSAIDs did not, or poorly, inhibit TA at concentrations of ≤ 10?3M. In intact rats, TA activity was stimulated 18-fold by pretreatment with mefenamic acid, 7-fold by dimethylsulfoxide and ibuprofen, 5-fold by acetylsalicylic and flufenamic acid, and doubled by benzydamine, amidopyrine, sodium salicylate and gold sodium thiosulphate. Indomethacin was somewhat less effective. Drug dosage was 20 per cent of the acute p.o. LD50, three times with 12-hourly intervals. Phenylbutazone, chloroquine and cyclophosphamide significantly increased TA activity also, though the dose was smaller relative to LD50. Adrenalectomy decreased the drug effects in almost all cases. Equi-toxic i.p. or p.o. doses of acetylsalicylic acid were equi-effective in intact rats. The action was dose-dependent and could be observed at a therapeutic dose. Elevated TA activities were determined up to 28 hrs after the last drug administration. Concomitant administration of glucose did not suppress the effect of mefenamic acid. The findings led to the following hypothesis: TA stimulation by NSAIDs depends on the actions of endogenous corticosteroids and, possibly, cyclic 3',5'-AMP. Similar processes might play a role in the anti-inflammatory mechanism of NSAIDs.
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