Pharmacokinetics and tissue distribution of a new heterocyclic N-phenylpiperazine derivative (LASSBio-581) in rats

This work investigated the pharmacokinetics of a new N-phenylpiperazine derivative (LASSBio-581), active on dopaminergic system. LASSBio-581 plasma concentrations were determined in rats after bolus administration of 10 mg/kg, i.v., 30 and 60 mg/kg, i.p. and p.o., by HPLC. Individual profiles were evaluated by non-compartmental and compartmental analysis using WinNonlin®. Protein binding by ultrafiltration showed free fraction of 29 ± 4%. The compound showed linear pharmacokinetics for the extravascular doses investigated. The oral bioavailability (∼25%) was approximately half of the intra-peritoneal one (∼47%). The 60 mg/kg oral dose showed an unusual profile with two peaks (1 and 6 h). A two-compartment model better described all plasma profiles. The Vd (0.8 ± 0.4 l/kg) and the t1/2 (1.2 ± 0.4 h) were smaller for i.v. than for the other routes. The CLtot was statistically similar for all three administration routes investigated (0.6 ± 0.2 l/(h kg)) (α = 0.05). The compound distribution into different organs, evaluated in tissue homogenates after i.v. administration, showed a higher penetration in lungs (51.0%), followed by the brain (39.2%), where the half-life was three times bigger than in the other tissues (1.9 h). The compound brain profile agreed with the central nervous system activity determined.