DISPOSITION AND METABOLISM OF (+)-5-METHYL-10,11-DIHYDRO-5H-DIBENZO[A,D] CYCLOHEPTEN-5,10-IMINE IN RATS, DOGS, AND MONKEYS

Abstract

The disposition and metabolism of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), a new agent with potent anticonvulsant, central sympathomimetic and apparent anxiolytic properties, was studied in rats, dogs and rhesus monkeys [Macaca mulatta] [3H]benzene-MK-801 was administered orally at a dose of 1 mg/kg. MK-801 was measured in plasma by GLC using a N detector; the overall sensitivity of the method was 3 ng/ml. Radioactivity was excreted mainly in urine of dogs and monkeys but fecal excretion in rats was also extensive. The apparent plasma t1/2 [half life] of MK-801 in the rat and dog was .apprx. 1 h. Maximal plasma levels of MK-801 in the rat, dog and monkey were 46 (0.5 h), 16 (0.25 h) and 10 (2 h) ng/ml, respectively. Radioactivity was extensively excreted in rat bile and was widely distributed among various tissues. Major metabolites of the drug in rat and dog urine were the 2- and 8-hydroxy analogs (rat) and the N-hydroxy derivative (dog).