title: Effect of bile on the oral absorption of halofantrine in polyethylene glycol 400 and polysorbate 80 formulations dosed to bile duct cannulated rats.
abstract: OBJECTIVE
  The aim of this study was to examine the effects of bile on the oral absorption of the poorly water-soluble compound, halofantrine, when administered to rats in vehicles consisting of the co-solvent polyethylene glycol 400 (PEG 400) alone or in mixtures with the surfactant polysorbate 80 (PS 80) (95:5; 85:15; 75:25 PEG 400:PS 80).
  
  
  METHODS
  Halofantrine (17.5 mg/kg) was administered to bile duct cannulated (BDC) and sham-operated rats in a fixed vehicle volume of 5 ml/kg.
  
  
  RESULTS
  The bioavailability of halofantrine was significantly lower in BDC rats when dosed with 0-5% PS 80 in PEG 400 compared with BDC rats dosed with >15% PS 80. Increasing the concentration of PS 80 to 15-100% eliminated this difference. A possible explanation for the lower bioavailability of halofantrine in BDC rats when dosed in pure PEG 400 could be the dilution of the vehicle by intestinal fluids, decreased transit time and precipitation in the gastrointestinal tract upon dilution of PEG 400.
  
  
  CONCLUSIONS
  The addition of PS 80 to the formulation increased its solubilising power upon dilution and may have inhibited precipitation and substituted the absence of bile above a certain level. Adjusting the level of surfactant in drug formulations could therefore be used to minimise variability in the bioavailability from co-solvent systems based upon differences in bile concentration between individuals.
authors.affiliation: Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Tønsberg
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.forename: Huiling
authors.initials: H
authors.lastname: Mu
authors.forename: Jette Bisgaard
authors.initials: JB
authors.lastname: Boll
authors.forename: Jette
authors.initials: J
authors.lastname: Jacobsen
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001652:Bile Ducts; D001682:Biological Availability; D011232:Chemical Precipitation; D004337:Drug Carriers / Q000493:pharmacokinetics*; D005772:Gastrointestinal Transit; D007408:Intestinal Absorption; D008297:Male; D010616:Phenanthrenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011136:Polysorbates / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014867:Water
chemical_list: D004337:Drug Carriers; D010616:Phenanthrenes; D011136:Polysorbates; D014867:Water; D011092:Polyethylene Glycols; C023768:halofantrine