Distribution of the methylpiperazinopyridobenzoxazepine derivative JL13, a potential antipsychotic, in rat brain

The brain uptake and distribution of the potential antipsychotic 5-(4-methylpiperazin-1 -yl)-8-chloro-pyrido[2,3][1,5]benzoxazepine fumarate (JL13) was examined in rats after neuropharmacologically active doses. Plasma and brain concentrations of the compound were measured by reversed-phase HPI-C with UV detection (210 nm). Clozapine was used as an internal standard. After an intraperitoneal dose of 10 mg kg(-1), the compound attained mean maximum plasma concentrations within 5 min of dosing, then declined with a mean elimination half-life of approximately 1 h. It rapidly crossed the blood-brain barrier and equilibrated with plasma, achieving mean maximum concentrations and area under the curve approximately 20-times those in plasma, with slight regional differences. Disappearance from whole brain almost paralleled its disappearance from plasma. There was a linear relationship between JL13 concentrations in plasma and brain regions, and in all tissues the concentrations of the compound increased almost linearly with the dose over the range of 5-20 mg kg(-1). It thus appears that JL13 brain pharmacokinetics parallels that in plasma, and that plasma concentrations accurately predict brain concentrations in rats.