title: Pharmacokinetic evaluation of LASSBio-579: an N-phenylpiperazine antipsychotic prototype.
abstract: This work aimed to investigate the pharmacokinetics of the N-phenylpiperazine antipsychotic prototype LASSBio-579 and to compare the results with those described for its bioisosteric derivative LASSBio-581. LASSBio-579 was administered to male Wistar rats as a 10 mg kg(-1) intravenous bolus and 30 and 60 mg kg(-1) intraperitoneal and 60 mg kg(-1) oral doses, and plasma concentrations were determined by a validated LC-MS/MS method. Individual plasma concentration-time profiles were evaluated by non-compartmental and compartmental analysis, using WinNonlin. LASSBio-579 plasma protein binding was 93 +/- 4%. After intravenous administration of 10 mg kg(-1), the Vd(ss) (0.6 +/- 0.2 L kg -1) and the t(1/2) (5.2 +/- 1.1 h) determined were smaller than those obtained after extravascular routes, but the CL(tot) (0.23 +/- 0.05 Lh(-1)kg(-1)) was statistically similar (alpha = 0.05). The intraperitoneal and oral bioavailability was around 1.7% and 0.6%, respectively. The plasma profiles obtained after intravenous and intraperitoneal administration of the compound were best fitted to a three-compartment and two-compartment lag-time open model, respectively. Brain tissue showed low penetration (6.3%) and t(1/2) of 1.1 h. Both the limited bioavailability and the lower brain penetration of LASSBio-579, in comparison with the LASSBio-581, suggest that its CNS activity may be due to a high receptor binding affinity or to a specific distribution into brain structures.
authors.affiliation: Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Av. Ipiranga, 2752, Porto Alegre, RS 90610-000, Brazil.
authors.forename: Daniela J
authors.initials: DJ
authors.lastname: Conrado
authors.forename: Hugo
authors.initials: H
authors.lastname: Verli
authors.forename: Gilda
authors.initials: G
authors.lastname: Neves
authors.forename: Carlos Alberto Manssour
authors.initials: CA
authors.lastname: Fraga
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Stela Maris Kuze
authors.initials: SM
authors.lastname: Rates
authors.forename: Teresa
authors.initials: T
authors.lastname: Dalla Costa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D014150:Antipsychotic Agents; D001798:Blood Proteins; C518328:LASSBio-579; C490224:LASSBio-581; D010879:Piperazines