Tasso Leandro, Neves Gilda, Menegatti Ricardo, Fraga Carlos Alberto Manssour, Barreiro Eliezer, Eifler-Lima Vera, Rates Stela Maris Kuze, Costa Teresa Dalla
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.
Eur J Pharm Sci. 2005 Oct;26(2):194-202. doi: 10.1016/j.ejps.2005.06.002.
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.
本研究考察了一种对多巴胺能系统有活性的新型N-苯基哌嗪衍生物（LASSBio-581）的药代动力学。通过高效液相色谱法（HPLC）测定大鼠静脉注射10mg/kg、腹腔注射30mg/kg和60mg/kg以及口服30mg/kg和60mg/kg后LASSBio-581的血浆浓度。使用WinNonlin通过非房室和房室分析评估个体药代动力学曲线。超滤法测定的蛋白结合率显示游离分数为29±4%。在所研究的血管外给药剂量下，该化合物呈现线性药代动力学特征。口服生物利用度（约25%）约为腹腔注射生物利用度（约47%）的一半。60mg/kg口服剂量呈现出不寻常的双峰曲线（1小时和6小时）。二室模型能更好地描述所有血浆曲线。静脉注射的分布容积（Vd）（0.8±0.4l/kg）和半衰期（t(1/2)）（1.2±0.4小时）比其他给药途径小。在所研究的三种给药途径中，总清除率（CL(tot)）在统计学上相似（0.6±0.2l/(h·kg)）（α=0.05）。静脉注射给药后在组织匀浆中评估该化合物在不同器官中的分布，结果显示在肺中的穿透率较高（51.0%），其次是脑（39.2%），脑内半衰期比其他组织大三倍（1.9小时）。该化合物在脑内的曲线与所确定的中枢神经系统活性相符。
