Rationale: Following an oral dose of risperidone (RSP), concentrations of its major metabolite 9-hydroxyrisperidone (9-OHRSP) were high in plasma and tissues but disproportionately lower in the brain compared to RSP, indicating that 9-OHRSP may have different pharmacokinetic properties. Objectives: To investigate non-compartmental pharmacokinetics of RSP and 9-OHRSP in plasma, brain and other tissues after separate administration of a single oral dose of 6 mg/kg RSP and 9-OHRSP to rats. Methods: Plasma, brain, liver, lung, kidney and spleen tissues were collected at pre-dose and at 0.5, 1, 2, 5, 6, 12, 24, 36 and 48 h post-dose, homogenized in saline and assayed for RSP and 9-OHRSP using a sensitive and specific liquid chromatography tandem mass spectrometry method. Results: The concentration-time curve of RSP and 9-OHRSP showed that they were readily absorbed and followed a multiphase elimination pattern. The terminal elimination half-life (\documentclass[12pt]{minimal}
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) of RSP after the RSP dose was longest in the liver (17.6 h) and shortest in the spleen (1.2 h). The \documentclass[12pt]{minimal}
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of 9-OHRSP after the RSP dose was shorter in plasma (3.4 h) and other tissues (~8–11 h) than that for RSP but it was longer in the spleen. However, the \documentclass[12pt]{minimal}
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of 9-OHRSP after the 9-OHRSP dose was shorter in most tissues as compared to the \documentclass[12pt]{minimal}
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of 9-OHRSP after the RSP dose. The area under the concentration-time curve (AUC) of RSP and 9-OHRSP was 6–67 times higher in the plasma and tissues than in the brain. AUCs of 9-OHRSP in tissues after the RSP dose were 2–5 times higher than those for RSP, except in the brain, where AUCs of RSP and 9-OHRSP were similar. Conclusion: Pharmacokinetics of 9-OHRSP in many tissues were different after RSP and 9-OHRSP doses. The reason for disproportionate brain levels of 9-OHRSP is not clear. The overall exposure to active drug in the brain as represented by AUC was similar after the RSP and 9-OHRSP doses and the 9-OHRSP is probably an equal contributor to the pharmacological actions of RSP.
