title: Inter-subject variability in intestinal drug solubility.
abstract: Variability in oral drug absorption is a well-known phenomenon, but it is often overlooked for its potential effects in oral drug delivery. Understanding the mechanisms behind absorption variability is crucial to understanding and predicting drug pharmacokinetics. In this study, the solubility of furosemide and dipyridamole - drugs known to have highly variable oral bioavailabilities - was investigated in individual ileostomy fluids from 10 subjects with ulcerative colitis. For comparison, drug solubility was also determined in pooled upper gastrointestinal fluids from healthy human subjects and simulated intestinal fluids. Ileostomy fluid characterization revealed high variability in buffer capacity and to a lesser degree for pH. Drug solubility in ileostomy fluids showed high variability. Correlation analysis revealed that dipyridamole solubility in these fluids is pH-dependent, whereas furosemide solubility was highly correlated to buffer capacity and pH. The implications of these results might partly explain the high variability in bioavailability in vivo, assuming that most of the observed variability is due to the absorption, and not the elimination, process.
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, UK.
authors.forename: Sarit Cohen
authors.initials: SC
authors.lastname: Rabbie
authors.affiliation: AstraZeneca, Alderley Park, Cheshire, UK.
authors.forename: Talia
authors.initials: T
authors.lastname: Flanagan
authors.affiliation: AstraZeneca, Alderley Park, Cheshire, UK.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Martin
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, UK. Electronic address: a.basit@ucl.ac.uk.
authors.forename: Abdul W
authors.initials: AW
authors.lastname: Basit
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D002021:Buffers; D003093:Colitis, Ulcerative / Q000378:metabolism / Q000601:surgery; D004176:Dipyridamole / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D005665:Furosemide / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007081:Ileostomy; D007408:Intestinal Absorption; D007419:Intestinal Secretions / Q000737:chemistry*; D008954:Models, Biological; D012995:Solubility
chemical_list: D002021:Buffers; D004176:Dipyridamole; D005665:Furosemide
keywords: Gastrointestinal fluids; Humans; Inter-subject variability; Oral absorption; Solubility