Disposition and Metabolic Fate of Tiaramide Hydrochloride,a New Anti-inflammatory Agent,in the Rat

1. A new non-steroidal anti-inflammatory agent, 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)[¹⁴C]acetyl]- 1-piperazine-ethanol hydrochloride (tiaramide hydrochloride) was rapidly absorbed after oral administration, reaching peak serum concn. in 20 min, with a half-life of 2·7 h. After intravenous injection the concn. of tiaramide decreased biphasically with half-lives of 0·2 and 1·3 h.

2. The metabolism of tiaramide, both in vivo and in vitro with rat liver 10 000 g supernatant fraction, gave three major metabolites identified as 1-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-piperazine (DETR), 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-piperazineacetic acid (TRAA), and 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-piperazineethanol 1-oxide (TRNO). The major serum metabolites were TRAA and TRNO.

3. After oral administration, unchanged tiaramide was found in high concn. in liver, kidney and lung. Tissue levels of tiaramide were 4–6 times higher than serum. Distribution of tiaramide in inflammatory tissue was also demonstrated. The major tissue metabolite was DETR and its concn. was 20–40 times higher in tissue than in serum.

4. Urinary excretion was almost complete within 24?h after oral administration. The major urinary metabolites were TRAA and TRNO.

5. Repeated administration of tiaramide did not alter the metabolism of tiarsmide.