Relationship between the brain levels and the anticonvulsant activity of denzimol after its acute and repeated administration to mice

The relationship between the brain concentration of denzimol and its anticonvulsant activity was studied in mice after acute and repeated administration (14 days) of this drug to mice. Anticonvulsant activity was assessed against maximal electroshock seizures (MES). When denzimol was administered at 30 mg/kg p.o. to repeatedly treated mice, its brain concentration and anticonvulsant activity were reduced in comparison to non-treated mice and t 1 2 β was significantly changed from 2.10 to 1.53 hr. Tonic hindlimb extension was completely abolished at a brain denzimol concentration higher than 15 mcg/g, whereas the minimum effective brain concentration was between 2–3 mcg/g both in acute and repeatedly treated animals. The brain concentration of denzimol is closely correlated with its anticonvulsant effect both in acute and repeatedly treated animals. Futhermore these findings seem to suggest that the decreased anticonvulsant activity of denzimol, following repeated administration, might be due to a development of pharmacokinetic tolerance.