Brain, plasma and tissue pharmacokinetics of risperidone and 9-hydroxyrisperidone after separate oral administration to rats.
BACKGROUND
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.


OBJECTIVE
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(1/2) ) of RSP after the RSP dose was longest in the liver (17.6 h) and shortest in the spleen (1.2 h). The t(1/2)of 9-OHRSP after the RSP dose was shorter in plasma (3.4 h) and other tissues (approximately 8-11 h) than that for RSP but it was longer in the spleen. However, the t(1/2) of 9-OHRSP after the 9-OHRSP dose was shorter in most tissues as compared to the t(1/2) 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.


CONCLUSIONS
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.
Aravagiri
Manickam
M
Psychopharmacology Unit, University of California at Los Angeles, VA Greater Los Angeles Healthcare System, Building 210, #15, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA. kannan@ucla.edu
Marder
Stephen R
SR
D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism*; D007555:Isoxazoles / Q000097:blood* / Q000493:pharmacokinetics*; D008297:Male; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000097:blood* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000097:blood* / Q000493:pharmacokinetics*; D012702:Serotonin Antagonists / Q000097:blood / Q000493:pharmacokinetics; D014018:Tissue Distribution / Q000502:physiology
D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D012702:Serotonin Antagonists; D018967:Risperidone; D000068882:Paliperidone Palmitate