Pharmacokinetics and tissue distribution of olanzapine in rats

The single dose pharmacokinetics of olanzapine in rats, following an oral d ose and its distribution in the brain and other tissues after repeated oral and intra-peritoneal (i.p.) administration, were studied. Olanzapine in pl asma, brain, liver, lung, kidney, spleen and fat was assayed at predose, 0. 25, 0.5, 1, 2, 5, 12, 24, 36, 48 h postoral dose of 6 mg/kg and after daily oral and i.p. doses of 0.25, 1, 3, and 6 mg/kg/day of olanzapine for 15 co nsecutive days by a sensitive and specific HPLC method with electrochemical detection. Olanzapine was readily absorbed and distributed in plasma and t issues as the peak concentrations were reached within similar to 45 min aft er the oral dose. The terminal half-life of olanzapine in plasma was 2.5 h and in tissues it ranged from 3 to 5.2 h. The area under the concentration- time curve (AUC(last)) was lowest in plasma and largest in liver and lung. The AUG,,,, of olanzapine was eight times larger in brain and three to 32 t imes larger in other tissues than that in plasma. After repeated oral doses , the plasma and tissue concentrations of olanzapine were generally higher than those after repeated i.p. doses. The liver and spleen had the highest concentrations after oral and i.p doses, respectively. In both cases, the t issue concentrations were four- to 46-fold higher than that in plasma and c orrelated with administered doses. Likewise, plasma concentrations strongly correlated with the simultaneous brain and tissue concentrations (r(2) > 0 .908, p < 0.0001). On average, the brain levels were 6.3-13.1 and 5.4-17.6 times higher than the corresponding plasma level after oral and i.p. doses, respectively. The tissue to plasma level ratio of olanzapine was higher in other tissues. The data indicated that olanzapine is rapidly absorbed and widely distributed in the tissues of rats after oral and i.p. administratio n. The plasma concentration appears to predict the simultaneous concentrati on in brain and other tissues. There was no marked localized accumulation o f olanzapine in any of the regions of the rat brain. Copyright (C) 1999 Joh n Wiley & Sons, Ltd.