Metabolism, disposition, and pharmacokinetics of tracazolate in rat and dog

The metabolism, disposition, and pharmacokinetics of tracazolate, (4-butylamino-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester), a novel anxiolytic agent, were studied in rat and dog following single oral and iv doses. Although tracazolate exhibits very good absorption (greater than 80%) in both species, it is extensively metabolized, accounting for low bioavailability. Excretion of 14C was rapid, with the kidney being the major organ of excretion. Tracazolate was not detected in the urine after iv doses even though measurable levels were found in blood, suggesting reabsorption of the compound by the renal tubules. The logarithm of the blood drug concentration vs. time data for both species was best described by a three-compartment open model. Mean t1/2 (beta) for tracazolate in the rat and dog were 14 and 10 hr, respectively. The distribution of radioactivity in rats showed that the concentrations of 14C and 14C-tracazolate were greater in tissues than in blood. Tracazolate was the predominant radioactive compound in brain during the first 6 hr and in fat for 96 hr. The extent and decay of tracazolate in fat strongly suggest that this tissue contributes significantly towards the equilibrium of drug between "deep body compartments" and blood. The major metabolite in blood was de-esterified tracazolate (ICI-US 7773) and in brain the gamma-ketotracazolate (ICI-US 10052).