Liposomes Coloaded with Elacridar and Tariquidar To Modulate the P-Glycoprotein at the Blood鈥揃rain Barrier

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• 作者：Rita Nieto Montesinos ; Arnaud B茅duneau ; Alf Lamprecht ; Yann Pellequer
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：November 2, 2015
• 年：2015
• 卷：12
• 期：11
• 页码：3829-3838
• 全文大小：395K
• ISSN：1543-8392

文摘

This study prepared three liposomal formulations coloaded with elacridar and tariquidar to overcome the P-glycoprotein-mediated efflux at the blood鈥揵rain barrier. Their pharmacokinetics, brain distribution, and impact on the model P-glycoprotein substrate, loperamide, were compared to those for the coadministration of free elacridar plus free tariquidar. After intravenous administration in rats, elacridar and tariquidar in conventional liposomes were rapidly cleared from the bloodstream. Their low levels in the brain did not improve the loperamide brain distribution. Although elacridar and tariquidar in PEGylated liposomes exhibited 2.6 and 1.9 longer half-lives than free elacridar and free tariquidar, respectively, neither their K_p for the brain nor the loperamide brain distribution was improved. However, the conjugation of OX26 F(ab鈥?₂ fragments to PEGylated liposomes increased the K_ps for the brain of elacridar and tariquidar by 1.4- and 2.1-fold, respectively, in comparison to both free P-gp modulators. Consequently, the K_p for the brain of loperamide increased by 2.7-fold. Moreover, the plasma pharmacokinetic parameters and liver distribution of loperamide were not modified by the PEGylated OX26 F(ab鈥?₂ immunoliposomes. Thus, this formulation represents a promising tool for modulating the P-glycoprotein-mediated efflux at the blood鈥揵rain barrier and could improve the brain uptake of any P-glycoprotein substrate that is intended to treat central nervous system diseases.