Metabolism of tiaramidein vitro: I. Oxidative metabolism of tiaramide by human and rat liver microsomes

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Abstract
N-Dealkylation and N-oxidation of tiaramide [an antiinflammatory agent] and of its major metabolite, TRAA [4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-piperazine acetic acid], by human and rat liver microsomes were investigated. With human liver microsomes, N-oxidation of tiaramide was 1.5-8.0 times faster than N-dealkylation. N-Oxidation of the metabolite, TRAA, by human liver microsomes was much slower than that of tiaramide. The high recovery of tertiary amine N-oxides in human urine after tiaramide dosing reflects the high activity of N-oxidation of tiaramide by human liver microsomes. Phenobarbital treatment of rats caused an increase in the liver microsomal N-dealkylation of tiaramide in vitro but had little effect on N-oxidation. 3-Methylcholanthrene treatment of rats caused decreased of both reactions. Metyrapone added to rat liver microsomes inhibited N-dealkylation more strongly than N-oxidation. Tetrahydrofuran and 7,8-benzoflavone inhibited N-dealkylation but had little effect on N-oxidation. Addition to the microsomal incubations of antisera against NADPH-cytochrome c reductase caused marked inhibition of N-dealkylation and slight inhibition of N-oxidation.