Kinetics of MK-801 and its effect on quinolinic acid-induced seizures and neurotoxicity in rats.
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 or 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 less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)
Vezzani
A
A
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Serafini
R
R
Stasi
M A
MA
Caccia
S
S
Conti
I
I
Tridico
R V
RV
Samanin
R
R
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003986:Dibenzocycloheptenes / Q000493:pharmacokinetics* / Q000494:pharmacology; D016291:Dizocilpine Maleate; D004569:Electroencephalography; D008297:Male; D011224:Prazosin / Q000494:pharmacology; D011725:Pyridines / Q000633:toxicity*; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects; D012640:Seizures / Q000517:prevention & control*
D000927:Anticonvulsants; D003986:Dibenzocycloheptenes; D011725:Pyridines; D011805:Quinolinic Acids; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D016291:Dizocilpine Maleate; D017378:Quinolinic Acid; D011224:Prazosin