title: Intestinal Permeability of β-Lapachone and Its Cyclodextrin Complexes and Physical Mixtures.
abstract: OBJECTIVE
  β-Lapachone (βLAP) is a promising, poorly soluble, antitumoral drug. βLAP combination with cyclodextrins (CDs) improves its solubility and dissolution but there is not enough information about the impact of cyclodextrins on βLAP intestinal permeability. The objectives of this work were to characterize βLAP intestinal permeability and to elucidate cyclodextrins effect on the dissolution properties and on the intestinal permeability. The final goal was to evaluate CDs influence on the oral absorption of βLAP.
  
  
  METHODS
  Binary systems (physical mixtures and inclusion complexes) including βLAP and CDs (β-cyclodextrin: βCD, random-methyl-β-cyclodextrin: RMβCD and sulfobutylether-β-cyclodextrin: SBEβCD) have been prepared and analysed by differential scanning calorimetry. βLAP (and its combinations with CDs) absorption rate coefficients and effective permeability values have been determined in vitro in MDCK or MDCK-Mdr1 monolayers and in situ in rat by a closed loop perfusion technique.
  
  
  RESULTS
  DSC results confirmed the formation of the inclusion complexes. βLAP-CDs inclusion complexes improve drug solubility and dissolution rate in comparison with physical mixtures. βLAP presented a high permeability value which can provide complete oral absorption. Its oral absorption is limited by its low solubility and dissolution rate. Cyclodextrin (both as physical mixtures and inclusion complexes) showed a positive effect on the intestinal permeability of βLAP. Complexation with CDs does not reduce βLAP intestinal permeability in spite of the potential negative effect of the reduction in free fraction of the drug.
  
  
  CONCLUSIONS
  The use of RMβCD or SBEβCD inclusion complexes could benefit βLAP oral absorption by enhancing its solubility, dissolution rate and permeability.
authors.affiliation: Department of Engineering, Pharmacy and Pharmaceutical Technology Area, Facultad de Farmacia, University Miguel Hernández, Elche, Carretera Alicante Valencia km 87, San Juan de Alicante, 03550, Alicante, Spain.|Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Mangas-Sanjuan
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, University of Valencia, Valencia, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Gutiérrez-Nieto
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, Campus Vida, University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Echezarreta-López
authors.affiliation: Department of Engineering, Pharmacy and Pharmaceutical Technology Area, Facultad de Farmacia, University Miguel Hernández, Elche, Carretera Alicante Valencia km 87, San Juan de Alicante, 03550, Alicante, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: González-Álvarez
authors.affiliation: Department of Engineering, Pharmacy and Pharmaceutical Technology Area, Facultad de Farmacia, University Miguel Hernández, Elche, Carretera Alicante Valencia km 87, San Juan de Alicante, 03550, Alicante, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: González-Álvarez
authors.affiliation: Department of Engineering, Pharmacy and Pharmaceutical Technology Area, Facultad de Farmacia, University Miguel Hernández, Elche, Carretera Alicante Valencia km 87, San Juan de Alicante, 03550, Alicante, Spain.
authors.forename: Vicente-Germán
authors.initials: VG
authors.lastname: Casabó
authors.affiliation: Department of Engineering, Pharmacy and Pharmaceutical Technology Area, Facultad de Farmacia, University Miguel Hernández, Elche, Carretera Alicante Valencia km 87, San Juan de Alicante, 03550, Alicante, Spain. mbermejo@goumh.umh.es.
authors.forename: Marival
authors.initials: M
authors.lastname: Bermejo
authors.affiliation: Pharmacy and Pharmaceutical Technology Department, Campus Vida, University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Mariana
authors.initials: M
authors.lastname: Landin
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism*; D002463:Cell Membrane Permeability; D004285:Dogs; D004339:Drug Compounding; D065546:Drug Liberation; D017097:Electric Impedance; D005079:Excipients / Q000737:chemistry*; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008745:Methylation; D009285:Naphthoquinones / Q000737:chemistry / Q000378:metabolism*; D010477:Perfusion; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D012995:Solubility; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000972:Antineoplastic Agents, Phytogenic; D005079:Excipients; D009285:Naphthoquinones; D011994:Recombinant Proteins; C103513:SBE7-beta-cyclodextrin; D047392:beta-Cyclodextrins; C014638:beta-lapachone; C031215:betadex