title: Direct in vivo evidence on the mechanism by which nanoparticles facilitate the absorption of a water insoluble, P-gp substrate.
abstract: Here we examine the mechanisms by which nanoparticles enable the oral absorption of water-insoluble, P-glycoprotein efflux pump (P-gp) substrates, without recourse to P-gp inhibitors. Both 200nm paclitaxel N-(2-phenoxyacetyl)-6-O-glycolchitosan (GCPh) nanoparticles (GCPh-PTX) and a simulated Taxol formulation, facilitate drug dissolution in biorelevant media, unlike paclitaxel nanocrystals. Verapamil (40mgkg-1) increased the oral absorption from low dose Taxol (6 or 10mgkg-1) by 100%, whereas the oral absorption from high dose Taxol (20mgkg-1) or low dose GCPh-PTX (6 or 10mgkg-1) was largely unchanged by verapamil. There was virtually no absorption from control paclitaxel nanocrystals (20mgkg-1). Imaging of ex-vivo rat ileum samples showed that fluorescently labelled GCPh nanoparticles are mucoadhesive and are taken up by ileum epithelial cells. GCPh nanoparticles were also found to open Caco-2 cell tight junctions. In conclusion, mucoadhesive, drug solubilising GCPh nanoparticles enable the oral absorption of paclitaxel via the saturation of the P-gp pump (by high local drug concentrations) and by particle uptake and tight junction opening mechanisms.
authors.affiliation: UCL School of Pharmacy, University College London, London, UK.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Soundararajan
authors.affiliation: UCL School of Pharmacy, University College London, London, UK.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: UCL School of Pharmacy, University College London, London, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Godfrey
authors.affiliation: UCL School of Pharmacy, University College London, London, UK.
authors.forename: Uchechukwu
authors.initials: U
authors.lastname: Odunze
authors.affiliation: UCL School of Pharmacy, University College London, London, UK.
authors.forename: Nancy
authors.initials: N
authors.lastname: Fereira
authors.affiliation: UCL School of Pharmacy, University College London, London, UK; Nanomerics Ltd., 1394 High Road, London N20 9YZ, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schätzlein
authors.affiliation: UCL School of Pharmacy, University College London, London, UK; Nanomerics Ltd., 1394 High Road, London N20 9YZ, UK. Electronic address: ijeoma.uchegbu@ucl.ac.uk.
authors.forename: Ijeoma
authors.initials: I
authors.lastname: Uchegbu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D048271:Chitosan / Q000737:chemistry / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism*; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D019108:Tight Junctions / Q000378:metabolism; D014700:Verapamil / Q000737:chemistry / Q000378:metabolism; D014867:Water / Q000737:chemistry*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004337:Drug Carriers; D014867:Water; D048271:Chitosan; D014700:Verapamil; D017239:Paclitaxel
keywords: Absorption; Biopharmaceutical Classification System; Chitosan amphiphile; N-(2-phenoxyacetamide)-6-O-glycolchitosan; Nanoparticle; Oral; Paclitaxel