Absorption and disposition of 14C-labelled oxiracetam in rat, dog and man.

Abstract

The absorption and disposition of the nootropic drug oxiracetam (4-hydroxy-2-oxo-pyrrolidine-1-yl acetamide) were studied in rats and dogs (10 mg/kg i.v. and 10, 50 and 3000 mg/kg p.o.) and two healthy male volunteers (800 mg p.o.) using a [14C]-labelled preparation. Peroral absorption of [14C]-oxiracetam was incomplete in rats (28-42%), high in dogs (81-90%) and intermediate in man (about 56%). The rate of absorption was high in all species. Elimination was biphasic and the concentration of total radioactivity in blood and plasma declined rapidly with an initial elimination half-life of 1-3 h in all species. The specific systemic exposure to [14C]-oxiracetam was lowest in the rat, intermediate in the dog and highest in man. In all species the systemically available radioactivity was nearly exclusively excreted in urine in the form of unmetabolized oxiracetam. Whole-body autoradiography and quantitative determination of the radioactivity in various organs following i.v. and p.o. administration of [14C]-oxiracetam to rats demonstrated extensive distribution of the compound with high levels in kidney, liver, lung and skin, and very low levels in the brain. The radioactivity was rapidly eliminated from the body and minimal accumulation was observed upon repeated administration of 10 mg/kg for 8 days. Levels in the brain were still low, but higher than following a single dose, indicating slow diffusion across the blood-brain barrier. In pregnant rats treated with [14C]-oxiracetam radioactivity passed reversibly and to a limited extent through the placenta into fetal tissue.