title: Pluronic P85 increases permeability of a broad spectrum of drugs in polarized BBMEC and Caco-2 cell monolayers.
abstract: OBJECTIVE
  Previous studies demonstrated that inhibition of P glycoprotein (P-gp) by Pluronic P85 (P85) block copolymer increases apical (AP) to basolateral (BL) transport of rhodamine 123 (R123) in the polarized monolayers of bovine brain microvessel endothelial cells (BBMEC) and Caco-2 cells. The present work examines the effects of P85 on the transport of fluorescein (Flu), doxorubicin (Dox), etoposide (Et), taxol (Tax), 3'-azido-3'-deoxythymidine (AZT), valproic acid (VPA) and loperamide (Lo) using BBMEC and Caco-2 monolayers as in vitro models of the blood brain barrier and intestinal epithelium respectively.
  
  
  METHODS
  Drug permeability studies were performed on the confluent BBMEC and Caco-2 cell monolayers mounted in Side-Bi-Side diffusion cells.
  
  
  RESULTS
  Exposure of the cells to P85 significantly enhanced AP to BL permeability coefficients of Flu, Tax, Dox and AZT in both cell models. Further, P85 enhanced AP to BL transport of Et, VPA and Lo in Caco-2 monolayers. No changes in the permeability coefficients of the paracellular marker mannitol were observed in the presence of the copolymer.
  
  
  CONCLUSIONS
  P85 increases AP to BL permeability in BBMEC and Caco-2 monolayers with respect to a broad panel of structurally diverse compounds, that were previously shown to be affected by P-gp and/ or multidrug resistance associated protein (MRP) efflux systems. Broad specificity of the block copolymer effects with respect to drugs and efflux systems appears to be a valuable property in view of developing pharmaceutical formulations to increase drug accumulation in selected organs and overcome both acquired and intrinsic drug resistance that limits the effectiveness of many chemotherapeutic agents.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Nebraska Medical Center, Omaha 68198-6025, USA.
authors.forename: E V
authors.initials: EV
authors.lastname: Batrakova
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: D W
authors.initials: DW
authors.lastname: Miller
authors.forename: A V
authors.initials: AV
authors.lastname: Kabanov
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000493:pharmacokinetics; D000818:Animals; D000930:Antidiarrheals / Q000493:pharmacokinetics; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects*; D018938:Caco-2 Cells / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D003287:Contrast Media / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000493:pharmacokinetics*; D019008:Drug Resistance, Neoplasm; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005047:Etoposide / Q000493:pharmacokinetics; D005079:Excipients / Q000494:pharmacology*; D019793:Fluorescein / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D008139:Loperamide / Q000493:pharmacokinetics; D008823:Micelles; D008833:Microcirculation / Q000187:drug effects; D017239:Paclitaxel / Q000493:pharmacokinetics; D020442:Poloxamer / Q000494:pharmacology*; D014316:Tritium; D014635:Valproic Acid / Q000493:pharmacokinetics; D015215:Zidovudine / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000930:Antidiarrheals; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D003287:Contrast Media; D004791:Enzyme Inhibitors; D005079:Excipients; D008823:Micelles; D014316:Tritium; D020442:Poloxamer; D015215:Zidovudine; D014635:Valproic Acid; D005047:Etoposide; D008139:Loperamide; D004317:Doxorubicin; D017239:Paclitaxel; D019793:Fluorescein