Brain, plasma and tissue pharmacokinetics of risperidone and 9-hydroxyrisperidone after separate oral administration to rats
| Autor: | Stephen R. Marder, Manickam Aravagiri |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Male
Oral dose medicine.medical_specialty 9-Hydroxyrisperidone Pharmacology toxicology Administration Oral Rats Sprague-Dawley Single oral dose Nuclear magnetic resonance Pharmacokinetics Oral administration Internal medicine Paliperidone Palmitate medicine Animals Tissue Distribution Respiratory system Pharmacology Chemistry Brain Isoxazoles Risperidone Rats Sprague dawley Pyrimidines Endocrinology Serotonin Antagonists Antipsychotic Agents |
| Zdroj: | Psychopharmacology. 159:424-431 |
| ISSN: | 1432-2072 0033-3158 |
| Popis: | 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 (\(\)\(t_{{\raise0.7ex\hbox{$1$} \!\mathord{\left/ {\vphantom {1 2}}\right.\kern-\nulldelimiterspace} \!\lower0.7ex\hbox{$2$}}} \) ) of RSP after the RSP dose was longest in the liver (17.6 h) and shortest in the spleen (1.2 h). The \(\)\(t_{{\raise0.7ex\hbox{$1$} \!\mathord{\left/ {\vphantom {1 2}}\right.\kern-\nulldelimiterspace} \!\lower0.7ex\hbox{$2$}}} \) 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 \(\)\(t_{{\raise0.7ex\hbox{$1$} \!\mathord{\left/ {\vphantom {1 2}}\right.\kern-\nulldelimiterspace} \!\lower0.7ex\hbox{$2$}}} \) of 9-OHRSP after the 9-OHRSP dose was shorter in most tissues as compared to the \(\)\(t_{{\raise0.7ex\hbox{$1$} \!\mathord{\left/ {\vphantom {1 2}}\right.\kern-\nulldelimiterspace} \!\lower0.7ex\hbox{$2$}}} \) 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. |
| Databáze: | OpenAIRE |
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