In dogs, rats, monkeys and rabbits, picumast (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin ) is eliminated from the plasma by metabolic clearance. Its main metabolic pathway is oxidation of the 3-methyl group of the coumarin ring. After oral administration, the parent compound accounted for less than 15% of the concentration of radioactivity in the plasma. In rats the hydroxylation product M2 was the main metabolite in the plasma; in the other species it was the carbonic acid M1. The hydroxylation of picumast was highly saturable, whereas further oxidation was independent of the dose in dogs and only slightly dose-dependent in rats. Picumast, M1 and M2 are pharmacologically active and potentially toxic. The sum of all three was defined as active compounds. The renal clearance of the active compounds, particularly of picumast, was very low. The terminal half-lives of the active compounds varied between 11 h in rats and 26 h in monkeys. The low plasma concentrations of other metabolites are at least partly due to their renal clearance. In dogs the bioavailability of the parent compound was 14%, the absorption of radioactivity 68%. Of radioactivity injected intravenously 54.8% was recovered from the faeces, 21.8% from the urine. The minimum toxic plasma concentrations of the active compounds were calculated from the minimum toxic dose (MTD) found in chronic or reproduction toxicity studies and the ratio Cl/f of total body clearance/bioavailability determined in the present investigations. The results showed that the differences between the MTDs in dogs and rats and on administration in rats by gavage or in the diet are largely due to differences in total body clearance and bioavailability.