title: The effects of pluronics block copolymers and Cremophor EL on intestinal lipoprotein processing and the potential link with P-glycoprotein in Caco-2 cells.
abstract: OBJECTIVE
  This investigation was performed to study the effects of Pluronic block copolymers and Cremophor EL on intestinal lipoprotein processing and to investigate a potential link between lipoprotein processing and P-glycoprotein.
  
  
  METHODS
  Caco-2 cells were used to monitor changes in lipoprotein production and secretion following exposure to excipients. Effects on P-glycoprotein were monitored using cyclosporin A as a model substrate.
  
  
  RESULTS
  A range of surfactants commonly used as pharmaceutical excipients in lipid-based oral drug delivery systems, including Pluronics block copolymers L81, P85, and F68 and Cremophor EL, inhibited intestinal lipoprotein secretion. The effects were concentration dependent and reversible. The mechanism of inhibition appears to be related to the assembly and secretion of lipoproteins rather than to initial intracellular triglyceride synthesis. A strong correlation was found between excipient-mediated inhibition of lipoprotein secretion and inhibition of P-glycoprotein efflux, implying a link between the two biochemical processes.
  
  
  CONCLUSIONS
  The ability of such bioactive excipients to simultaneously manipulate different cellular processes must be considered in selecting excipients for oral drug delivery systems. Such information is particularly relevant when the drug is lipophilic, a candidate for P-glycoprotein efflux, and where intestinal lymphatic targeting via chylomicron stimulation is desirable.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Technology, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Fergal
authors.initials: F
authors.lastname: Seeballuck
authors.forename: Marianne B
authors.initials: MB
authors.lastname: Ashford
authors.forename: Caitriona M
authors.initials: CM
authors.lastname: O'Driscoll
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018938:Caco-2 Cells; D002470:Cell Survival / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005990:Glycerol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008074:Lipoproteins / Q000378:metabolism; D020442:Poloxamer / Q000493:pharmacokinetics*; D011108:Polymers / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004338:Drug Combinations; D008074:Lipoproteins; D011108:Polymers; D020442:Poloxamer; C000515:cremophor EL; D005990:Glycerol