ISSN:
1432-2072
Keywords:
Key words Risperidone
;
9-Hydroxy-risperidone
;
Antipsychotics
;
Tissue distribution
;
Regional brain distribution
;
Brain to plasma level ratio
;
Dose-tissue level relationship
;
Rat
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
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 r s ≥ 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 r s≥ 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 r s ≥ 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 (r s ≥ 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/s002130050726
