THE METABOLISM AND EXCRETION OF RISPERIDONE AFTER ORAL-ADMINISTRATIONIN RATS AND DOGS

The metabolism and excretion of risperidone (RIS; e-3-yl)-1-piperidiny l]ethyl]-6,7,8,9-tetrahydro-2- methyl-4H-pyrido[1,2-a]pyrimidin-4-one) , a novel antipsychotic drug, were studied after single po administrat ion of radiolabeled RIS to rats and dogs. In rats, the excretion of th e radioactivity was very rapid. The predominant excretion in rat feces (78-82% of the dose) was related to an extensive biliary excretion of metabolites (72-79% of the dose), only a small part of which underwen t enterohepatic circulation. In dogs, about 92% of the dose had been e xcreted after one week, and the fractions recovered in the urine and f eces were comparable. Only a few percent of a po dose was excreted as unchanged RIS in rats as well as in dogs. Major metabolic pathways of RIS in rats and dogs were the same as those in humans. The main pathwa y was the hydroxylation at the alicyclic part of the etrahydro-2-methy l-4H-pyrido[1,2-a]pyrimidin-4-one moiety. The resulting 9-hydroxy-risp eridone (9-OH-RIS) was the main metabolite in the excreta of dogs. In rats, the metabolism was more extensive, resulting in dihydroxy-RIS an d hydroxy-keto Rls, which were eliminated mainly via the bile. However , in male and in female rats, just as in dogs and humans, the active m etabolite 9-OH-RIS was by far the main plasma metabolite. Other major metabolic pathways were the oxidative dealkylation at the piperidine n itrogen and the scission of the isoxazole in the benzisoxazole ring sy stem. The latter pathway appeared to be effected primarily by the inte stinal microflora. The mass balance of the metabolites of RIS in dogs was dose independent from 0.05 to 1.25 mg/kg and was similar to that i n humans.