title: Liposomes Coloaded with Elacridar and Tariquidar To Modulate the P-Glycoprotein at the Blood-Brain Barrier.
abstract: This study prepared three liposomal formulations coloaded with elacridar and tariquidar to overcome the P-glycoprotein-mediated efflux at the blood-brain 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 Kp for the brain nor the loperamide brain distribution was improved. However, the conjugation of OX26 F(ab')2 fragments to PEGylated liposomes increased the Kps 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 Kp 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')2 immunoliposomes. Thus, this formulation represents a promising tool for modulating the P-glycoprotein-mediated efflux at the blood-brain barrier and could improve the brain uptake of any P-glycoprotein substrate that is intended to treat central nervous system diseases.
authors.affiliation: Laboratory of Pharmaceutical Engineering, EA 4267, University of Franche-Comté , 25000 Besançon, France.
authors.forename: Rita
authors.initials: R
authors.lastname: Nieto Montesinos
authors.affiliation: Laboratory of Pharmaceutical Engineering, EA 4267, University of Franche-Comté , 25000 Besançon, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Béduneau
authors.affiliation: Laboratory of Pharmaceutical Engineering, EA 4267, University of Franche-Comté , 25000 Besançon, France.|Laboratory of Pharmaceutical Technology and Biopharmaceutics, University of Bonn , 53113 Bonn, Germany.
authors.forename: Alf
authors.initials: A
authors.lastname: Lamprecht
authors.affiliation: Laboratory of Pharmaceutical Engineering, EA 4267, University of Franche-Comté , 25000 Besançon, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Pellequer
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000166:Acridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000930:Antidiarrheals / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects; D008081:Liposomes; D008139:Loperamide / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000166:Acridines; D000930:Antidiarrheals; D008081:Liposomes; D011804:Quinolines; D044005:Tetrahydroisoquinolines; D008139:Loperamide; C402343:tariquidar; C083501:Elacridar
keywords: P-glycoprotein; P-glycoprotein modulators; blood−brain barrier; coencapsulation; immunoliposomes