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-piperazineethanol 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 micron.