title: Distribution after repeated oral administration of different dose levels of risperidone and 9-hydroxy-risperidone in the brain and other tissues of rat.
abstract: Rats were treated with daily oral doses of 1, 4, and 6 mg/kg risperidone (RSP) and its metabolite, 9-hydroxy-risperidone (9-OH-RSP), for 15 consecutive days. Concentrations of RSP and 9-OH-RSP were measured in plasma, brain, liver, kidney, lungs and fat tissue by high-performance liquid chromatography with electrochemical detection. Non-specific distribution of RSP and 9-OH-RSP in various brain regions was also studied after administration of 6 mg/kg per day oral dose for 15 days. After RSP treatment, concentrations of 9-OH-RSP were higher than those of RSP in plasma and tissues except in brain, where both compounds were present in nearly equal concentrations. Similarly, after 9-OH-RSP treatment, levels of 9-OH-RSP were higher than levels of either RSP or 9-OH-RSP or the sum of RSP and 9-OH-RSP levels measured after treatment with RSP. There was a moderate relationship between RSP dose and tissue levels of RSP and 9-OH-RSP (all rs > or = 0.62, P < 0.01), except in fat. There was also a strong relationship between the dose and tissue levels of 9-OH-RSP (all rs > or = 0.68, P < 0.005). A significant relationship was found between plasma levels of RSP and brain levels of RSP and 9-OH-RSP (all rs > or = 0.57, P < 0.03) after treatment with RSP. After 9-OH-RSP treatment, a much stronger relationship was observed between plasma and brain 9-OH-RSP levels (rs > or = 0.90, P < 0.005). The plasma concentrations of RSP and 9-OH-RSP appear to reflect their concentrations in brain. The tissue-to-plasma ratios of RSP and 9-OH-RSP were relatively low compared to other antipsychotics. In liver, kidney and lung the tissue to plasma ratio for RSP and 9-OH-RSP after treating with RSP ranged from 0.85 to 3.4. The brain to plasma ratio for RSP and 9-OH-RSP was several-fold lower than that in peripheral tissues. After RSP administration, the mean brain to plasma level ratio for RSP was 0.22, and for 9-OH-RSP to it was 0.04. The brain to plasma ratio of 9-OH-RSP after giving 9-OH-RSP was similarly low (0.04). The low brain/plasma ratio of high potency RSP and 9-OH-RSP may in part be due to their low lipophilicity, log P = 3.04 and 2.32, respectively, resulting in limited non-specific accumulation in brain tissue.
authors.affiliation: Psychopharmacology Unit, University of California at Los Angeles, West Los Angeles VAMC, 90073, USA. kannan@ucla.edu
authors.forename: M
authors.initials: M
authors.lastname: Aravagiri
authors.forename: A
authors.initials: A
authors.lastname: Yuwiler
authors.forename: S R
authors.initials: SR
authors.lastname: Marder
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism*; D007555:Isoxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D000068882:Paliperidone Palmitate; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D018967:Risperidone; D000068882:Paliperidone Palmitate