title: Identification of key factors affecting the oral absorption of salts of lipophilic weak acids: a case example.
abstract: OBJECTIVE
  Evaluate the ability of biorelevant media to adequately predict solubility in human gastrointestinal aspirates collected in the fasted state for the sodium salt of a highly dosed, Biopharmaceutics Classification System II (BCS II) compound with weakly acidic properties (L-870,810, pKa 7.3, HA (5-(1,1-dioxothiazinan-2-yl)-N-((4-fluorophenyl)methyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide)). Identify key luminal processes that dictate the behaviour of sodium salt of HA (NaA), after single-dose administrations of high (relatively to solubility limit) doses corresponding to 400 and 800 mg of HA in the fasted state.
  
  
  METHODS
  Aspirates from stomach and upper small intestine were collected from eight healthy fasted adults, after administration of 240 ml of water. Solubilities of NaA and HA were measured in aspirated samples and biorelevant media. Dissolution experiments of NaA granules were performed in biorelevant media. Prediction of oral pharmacokinetics was evaluated in silico using Stella software.
  
  
  RESULTS
  Equilibrium solubility of NaA in fluids aspirated from the upper gastrointestinal tract is more transient than of HA. Solubility in upper gastrointestinal lumen was adequately estimated by data in biorelevant media. Supersaturation, followed by precipitation, which did not fully revert to the equilibrium solubility of HA, was observed during the dissolution of NaA granules in biorelevant media. Physiologically based pharmacokinetic modelling indicated that while intragastric processes had no significant impact on absorption kinetics, dissolution kinetics, kinetic solubility, radial transport rates and, for the 800-mg dose, precipitation kinetics in the small intestine had the greatest impact on absorption profiles.
  
  
  CONCLUSIONS
  Adequate prediction of the average plasma profile, after administration of NaA, required consideration of region-dependent dissolution rates and/or solubilisation.
authors.affiliation: Faculty of Pharmacy, National & Kapodistrian University of Athens, Athens, Greece.
authors.forename: Orestis
authors.initials: O
authors.lastname: Petrakis
authors.forename: Maria
authors.initials: M
authors.lastname: Vertzoni
authors.forename: Alexandros
authors.initials: A
authors.lastname: Angelou
authors.forename: Filippos
authors.initials: F
authors.lastname: Kesisoglou
authors.forename: Kimberly
authors.initials: K
authors.lastname: Bentz
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Goumas
authors.forename: Christos
authors.initials: C
authors.lastname: Reppas
mesh_terms: D000143:Acids / Q000737:chemistry*; D003499:Cyclic S-Oxides / Q000737:chemistry* / Q000493:pharmacokinetics; D065546:Drug Liberation; D006863:Hydrogen-Ion Concentration; D008954:Models, Biological; D009287:Naphthyridines / Q000737:chemistry* / Q000493:pharmacokinetics; D012492:Salts / Q000737:chemistry*; D012995:Solubility
chemical_list: D000143:Acids; D003499:Cyclic S-Oxides; D009287:Naphthyridines; D012492:Salts
keywords: dissolution; human aspirates; oral pharmacokinetics; salts of weak acids; solubility