title: In Vitro and In Situ evaluation of pH-dependence of atazanavir intestinal permeability and interactions with acid-reducing agents.
abstract: OBJECTIVE
  The objectives of this study were to evaluate the effects of intestinal lumen pH, food intake, and acid-reducing agents on the intestinal permeability of atazanavir, an HIV-1 protease inhibitor.
  
  
  METHODS
  Atazanavir permeability across Caco-2 cell monolayers (P app) and in situ steady-state permeability across rat jejunum and ileum (P eff) were evaluated in buffers of varied pH (4.5-8.5), in fasted- or fed-state simulated intestinal fluid, or in presence of acid-reducing drugs (e.g., omeprazole).
  
  
  RESULTS
  In vitro accumulation and apical-to-basolateral P app of atazanavir increased with decreasing pH. This effect appeared to be associated with lower atazanavir efflux by P-glycoprotein at acidic pH (5.5) compared to neutral pH. In situ atazanavir P eff across rat jejunum and ileum also decreased 2.7 and 2.3-fold, respectively, when pH was increased from 4.5 to 8.5. Several acid-reducing agents (e.g., omeprazole) moderately inhibited atazanavir efflux in Caco-2 monolayers; however, this effect was not observed in situ. Fed-state buffer significantly increased atazanavir apical-to-basolateral P app (p < 0.001) and in situ P eff (p < 0.05) compared to fasted-state buffer.
  
  
  CONCLUSIONS
  Atazanavir permeability is sensitive to changes in intestinal lumen pH. This pH-sensitivity may contribute to atazanavir clinical interactions with acid-reducing agents and variable oral bioavailability.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Room 1001, Toronto, Ontario, M5S 3M2, Canada.
authors.forename: Olena
authors.initials: O
authors.lastname: Kis
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Walmsley
authors.forename: Reina
authors.initials: R
authors.lastname: Bendayan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000143:Acids / Q000737:chemistry; D000818:Animals; D000069446:Atazanavir Sulfate; D018938:Caco-2 Cells; D004347:Drug Interactions; D004435:Eating; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D009842:Oligopeptides / Q000493:pharmacokinetics* / Q000494:pharmacology; D009853:Omeprazole / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000493:pharmacokinetics* / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D019163:Reducing Agents / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000143:Acids; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D054328:Proton Pump Inhibitors; D011725:Pyridines; D019163:Reducing Agents; D000069446:Atazanavir Sulfate; D009853:Omeprazole