title: Enhanced transport of a novel anti-HIV agent--cosalane and its congeners across human intestinal epithelial (Caco-2) cell monolayers.
abstract: OBJECTIVE
  Cosalane is a potent inhibitor of HIV replication with activity against a broad range of viral targets. However, oral bioavailability of this highly lipophilic compound is extremely poor (<1%). The purpose of this study is to screen a variety of permeation enhancers (cyclodextrin derivatives, cremophor EL, bile salts and mixed micelles) for their ability to enhance the transport of cosalane and its analogs/prodrugs across Caco-2 cell monolayers.
  
  
  METHODS
  Cosalane and its different analogs/prodrugs were synthesized and their physicochemical properties were determined. Caco-2 cells were cultured at a density of 66,000 cells/cm(2) either on collagen coated clear polyester membranes or Transwell inserts. Side-bi-side diffusion cells and Transwell inserts were employed to study for the transport of cosalane and its analogs/prodrugs with various permeation enhancers across Caco-2 cell monolayers.
  
  
  RESULTS
  Permeabilities of EH-3-39, EH-3-55 and EH-3-57 significantly improved compared to that of cosalane in the presence of bile salt, sodium desoxycholate. Among the various cyclodextrins studied, hydroxypropyl beta cyclodextrin (HP-beta-CD) and dimethyl beta cyclodextrin (DM-beta-CD) exhibited 22.3-fold and 19-fold permeability enhancement of cosalane respectively across Caco-2 cell monolayers. Sodium desoxycholate (10 mM) also showed a remarkable (105-fold) enhancement on the permeability of cosalane (P(app) 11.72+/-3.31 x 10(-6) cm/s) without causing any measurable cellular damage. Cremophor EL resulted in higher transport of 14C mannitol. The mechanism of enhancement effect can be mainly attributed to the alteration of membrane fluidity by cyclodextrin and opening of tight junctions by cremophor EL.
  
  
  CONCLUSIONS
  Among the enhancers tested, 10 mM sodium desoxycholate and HP-beta-CD appear to be viable candidates for further development of an oral formulation of cosalane and its congeners.
authors.affiliation: Drug Metabolism, Wyeth Research, Pearl River, NY, USA.
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Udata
authors.forename: Jignesh
authors.initials: J
authors.lastname: Patel
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Pal
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Hejchman
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001312:Aurintricarboxylic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D001692:Biological Transport; D018938:Caco-2 Cells; D003505:Cyclodextrins / Q000008:administration & dosage; D005990:Glycerol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D010539:Permeability; D012995:Solubility
chemical_list: D019380:Anti-HIV Agents; D003505:Cyclodextrins; C083060:cosalane; D001312:Aurintricarboxylic Acid; C000515:cremophor EL; D005990:Glycerol