Species Differences in Metabolism of Tiaramide Hydrochloride,a New Anti-inflammatory Agent

1. Urinary excretion of the radioactivity in 24?h after oral administration of ¹⁴C]tiaramide hydrochloride was 67% of the dose in mice, 59% in rats, 41% in dogs and 74% in monkeys.

2. The serum half-lives of tiaramide after intravenous administration were approximately 0·2?h in mice, 0·8?h in rats and 0·5?h in dogs.

3. Marked species variations were noted in the composition of metabolites in the serum and urinary radioactivity. The major metabolites found were 1-(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-piperazine (DETR) and 4-(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-piperazineacetic acid (TRAA) in mice, TRAA and 4-(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-pipera-zineethanol 1-oxide (TRNO) in rats, TRNO and tiaramide-O-glucuronide (TR-O-Glu) in dogs, and TRAA and TR-O-Glu in monkeys.

4. The binding of tiaramide to plasma protein of the various species of animals and human was about 24–34% and the extent of the binding of tiaramide to human plasma protein was independent of drug concentration within the range of 1–100 μM.