Pharmacokinetics, tissue distribution and bioavailability of clozapine solid lipid nanoparticles after intravenous and intraduodenal administration

Clozapine, a lipophilic effective atypical antipsychotic drug, has very poor oral bioavailability (< 27%) due to first pass effect. Clozapine solid lipid nanoparticles have been developed using various triglycerides (trimyristin, tripalmitin and tristearin), soylecithin 95%, poloxamer 188 and stearylamine as a positive charge inducer by hot homogenization followed by ultrasonication method. Particle size and charge measurements were made with Malvern Zetasizer. Pharmacokinetics of clozapine incorporated in solid lipid nanoparticles (SLNs), after intravenous (i.v.) administration to conscious male Wistar rats were studied. The aim of this research was to find out whether the bioavailability of clozapine can be improved by administering clozapine SLN duodenally to rats. Tissue distribution studies of clozapine SLN and suspension were carried out in Swiss albino mice. Average size and zeta potential of SLNs of different lipids with stearylamine ranged from 96.7 +/- 3.8 to 163.3 +/- 0.7 nm and 21.3 +/- 1.3 to 33.2 +/- 0.6 mV, respectively. AUC((0-infinity)) was increased (up to 2.91-fold) and clearance was decreased (up to 2.93-fold) when clozapine entrapped in SLNs with stearylamine were administered intravenously. Bioavailability of clozapine SLNs were 2.45- to 4.51-fold after intraduodenal administration compared with that of clozapine suspension. In tested organs, the AUC and MRT of clozapine SLNs were higher than those of clozapine suspension especially in brain and reticuloendothelial cell-containing organs. These results indicate that SLN are suitable drug delivery system for the improvement of bioavailability of lipophilic drugs such as clozapine. (c) 2005 Elsevier B.V. All rights reserved.