DISTRIBUTION AFTER REPEATED ORAL-ADMINISTRATION OF DIFFERENT DOSE LEVELS OF RISPERIDONE AND 9-HYDROXY RISPERIDONE IN THE BRAIN AND OTHER TISSUES OF RAT

Rats were treated with daily oral doses of 1, 4, and 6 mg/kg risperido ne (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 di stribution of RSP and 9-OH-RSP in various brain regions was also studi ed after administration of 6 mg/kg per day oral dose for 15 days. Afte r RSP treatment, concentrations of 9-OH-RSP were higher than those of RSP in plasma and tissues except in brain, where both compounds were p resent in nearly equal concentrations. Similarly, after 9-OH-RSP treat ment, 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 wi th RSP. There was a moderate relationship between RSP dose and tissue levels of RSP and 9-OH-RSP (all r(s) greater than or equal to 0.62, P < 0.01), except in fat. There was also a strong relationship between t he dose and tissue levels of 9-OH-RSP (all r(s) 2 0.68, P < 0.005). A significant relationship was found between plasma levels of RSP and br ain levels of RSP and 9-OH-RSP (all r(s) greater than or equal to 0.57 1 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) greater than or equal to 0.90, P < 0.005). The plasma con centrations 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 relati vely low compared to other antipsychotics. In liver, kidney and lung t he 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-R SP was several-fold lower than that in peripheral tissues. After RSP a dministration, 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 parr be due to their low lipophilicity, log P = 3.04 and 2.32, respectively, resulting in limi ted non-specific accumulation in brain tissue.