title: Increased brain uptake of venlafaxine loaded solid lipid nanoparticles by overcoming the efflux function and expression of P-gp.
abstract: Venlafaxine (VLX) could be pumped out of the brain by P-glycoprotein (P-gp). Moreover, the expression of P-gp distributed in blood-brain barrier could be significantly induced by VLX. Thus, P-gp could be considered as the nature barrier for delivering of VLX to the brain. The aim of this study was to investigate whether the efflux function and increased expression of P-gp could be reversed by utilizing solid lipid nanoparticles (SLN). VLX solid lipid nanoparticles (VLX - SLN) were prepared and evaluated. Pharmacokinetics and brain distribution of VLX in different formulations were conducted after oral or intravenous administration. P-gp efflux function to VLX was evaluated by the brain uptake amount of VLX, while P-gp expression was investigated by Western blotting. Results indicated that the entrapment, mean size and zata potential of VLX - SLN was 74.9 ± 3.0 %, 186.3 ± 69.26 nm and -22.8 ± 7.78 mv, respectively. After vein injection of VLX formulations, the brain uptake amount of VLX from VLX - SLN was significantly higher than that of VLX solution, VLX solution with empty SLN (VLX+ empty SLN) and VLX solution with Verapamil (VLX + Ver), respectively. Furthermore, the protein mass of P-gp in VLX - SLN treated group was the lowest among all the investigated groups. These results indicated that SLN could overcome P-gp and achieve brain target by intravenous administration.
authors.affiliation: Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou, 730000, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Zhang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Rao
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.forename: Hongyan
authors.initials: H
authors.lastname: Qin
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Wei
authors.forename: Xin'an
authors.initials: X
authors.lastname: Wu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D061605:Administration, Intravenous; D000284:Administration, Oral; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004337:Drug Carriers; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010316:Particle Size; D013499:Surface Properties; D014018:Tissue Distribution; D000069470:Venlafaxine Hydrochloride / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004337:Drug Carriers; D008055:Lipids; D000069470:Venlafaxine Hydrochloride