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 10mg/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 ( approximately 25%) was approximately half of the intra-peritoneal one ( approximately 47%). The 60 mg/kg oral dose showed an unusual profile with two peaks (1 and 6h). A two-compartment model better described all plasma profiles. The Vd (0.8+/-0.4l/kg) and the t(1/2) (1.2+/-0.4h) were smaller for i.v. than for the other routes. The CL(tot) was statistically similar for all three administration routes investigated (0.6+/-0.2l/(hkg)) (alpha=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 (1.9h). The compound brain profile agreed with the central nervous system activity determined.
Tasso
Leandro
L
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga, 2752 Porto Alegre, RS 90.610-000, Brazil.
Neves
Gilda
G
Menegatti
Ricardo
R
Fraga
Carlos Alberto Manssour
CA
Barreiro
Eliezer
E
Eifler-Lima
Vera
V
Rates
Stela Maris Kuze
SM
Costa
Teresa Dalla
TD
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism*; D006207:Half-Life; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D008297:Male; D008657:Metabolic Clearance Rate; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D014150:Antipsychotic Agents; C490224:LASSBio-581; D010879:Piperazines