title: Reciprocal competition between lipid nanocapsules and P-gp for paclitaxel transport across Caco-2 cells.
abstract: Lipid nanocapsules (LNCs) have been shown to improve paclitaxel (Ptx) bioavailability and transport across an intestinal barrier model. In the present study, the interaction between P-glycoprotein (P-gp) and LNC transport across Caco-2 cells are investigated. Transport experiments have been performed on Caco-2 cells displaying different P-gp activities (early and later cell passages). The permeability of Ptx encapsulated in LNCs has been studied in the presence of P-gp inhibitors (verapamil and vinblastin) or unloaded LNCs. The uptake of dye-labelled LNCs was also observed in the presence of the same inhibitors. It was found that the permeability of Ptx varied depending on the passages with later ones showing higher absolute values (5.74+/-1.21 cms(-1) vs 133.41+/-5.74 cms(-1)). P-gp inhibition obtained with verapamil or vinblastin improved Ptx transport up to 98%. LNCs have also demonstrated their capacity to increase their own transport. Experiments performed with dye-labelled LNCs demonstrated an enhancement of the uptake of dye (Nile red), only in the presence of verapamil. These results demonstrated an effect of P-gp on the transport of Ptx when loaded in LNCs and support a direct effect of P-gp on their endocytosis in Caco-2 cells. These finding may assist in the development of new nanomedicine for oral administration.
authors.affiliation: Ethypharm, Saint-Cloud Cedex, France.
authors.forename: E
authors.initials: E
authors.lastname: Roger
authors.forename: F
authors.initials: F
authors.lastname: Lagarce
authors.forename: E
authors.initials: E
authors.lastname: Garcion
authors.forename: J-P
authors.initials: JP
authors.lastname: Benoit
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D001682:Biological Availability; D001692:Biological Transport; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D004337:Drug Carriers; D004339:Drug Compounding; D004705:Endocytosis; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D053769:Nanocapsules; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D053769:Nanocapsules; D017239:Paclitaxel