MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclo-hepten-5,10-imine maleate], a noncompetitive antagonist of the N-methyl-D-aspartate-type of excitatory aminoacid receptors, was measured in plasma and brain tissues after i.p. administration to rats by using a novel high-performance liquid chromatography assay. The drug reached maximal concentrations in plasma and brain within 10 to 30 min of injection (2 mg/kg) with an elimination half-life of 1.9 and 2.05 hr, respectively. Mean ratio of brain area concentration-time curve to plasma area concentration time curve was 12.5, referring to total plasma concentrations. MK-801 distributed almost equally between plasma and red cells (mean blood-to-plasma ratio averaged (1.2 ± 0.2 when calculated 30 and 180 min from drug administration). Plasma and brain concentrations of MK-801 rose almost linearly from 0.5 to 4 mg/kg 30 min after injection and the brain-to-plasma ratio (12.9 ± 2.8) was constant in the dose range studied. The distribution of the drug in various brain regions 30 and 180 min after 2 mg/kg i.p. showed no preferential concentration of retention in any of the areas studied. The anticonvulsant effect of MK-801 was evaluated against limbic seizures (measured by EEG) induced by intrahippocampal injection of 120 nmol of quinolinic acid, an agonist of the N-methyl-D-aspartate-type receptors, in freely moving rats. At 0.25 and 0.5 mg/kg, MK-801 significantly lowered by 71 to 77% the number of seizures and by 80% the total time spent in seizures (P <.01). The onset of seizures was significantly delayed only at 0.5 mg/kg (P <.05). Prazosin (3 mg/kg), a dose which did not modify susceptibility to quinolinic acid seizures, prevented the effect of 0.5 mg/kg on the various seizure parameters. Cell death induced by intrahippocampal injection of 120 nmol of quinolinic acid was prevented in some animals at 1 mg/kg of MK-801 whereas in the remaining animals given this and lower doses pyramidal cell degeneration was observed (particularly in the CA1 subfield).
|Number of pages||6|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|Publication status||Published - 1989|
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