THE METABOLISM AND EXCRETION OF RISPERIDONE AFTER ORAL-ADMINISTRATION IN RATS AND DOGS

The metabolism and excretion of risperidone (RIS; 3-[2-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl]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 administration of radiolabeled RIS to rats and dogs. In rats, the excretion of the 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 underwent enterohepatic circulation. In dogs, about 92% of the dose had been excreted after one week, and the fractions recovered in the urine and feces 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 pathway was the hydroxylation at the alicyclic part of the 6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one moiety. The resulting 9-hydroxy-risperidone (9-OH-RIS) was the main metabolite in the excreta of dogs. In rats, the metabolism was more extensive, resulting in dihydroxy-RIS and 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 metabolite 9-OH-RIS was by far the main plasma metabolite. Other major metabolic pathways were the oxidative dealkylation at the piperidine nitrogen and the scission of the isoxazole in the benzisoxazole ring system. The latter pathway appeared to be effected primarily by the intestinal 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 in humans.