title: Lipid absorption triggers drug supersaturation at the intestinal unstirred water layer and promotes drug absorption from mixed micelles.
abstract: OBJECTIVE
  To evaluate the potential for the acidic intestinal unstirred water layer (UWL) to induce drug supersaturation and enhance drug absorption from intestinal mixed micelles, via the promotion of fatty acid absorption.
  
  
  METHODS
  Using a single-pass rat jejunal perfusion model, the absorptive-flux of cinnarizine and (3)H-oleic acid from oleic acid-containing intestinal mixed micelles was assessed under normal acidic microclimate conditions and conditions where the acidic microclimate was attenuated via the co-administration of amiloride. As a control, the absorptive-flux of cinnarizine from micelles of Brij® 97 (a non-ionizable, non-absorbable surfactant) was assessed in the absence and presence of amiloride. Cinnarizine solubility was evaluated under conditions of decreasing pH and decreasing micellar lipid content to assess likely changes in solubilization and thermodynamic activity during micellar passage across the UWL.
  
  
  RESULTS
  In the presence of amiloride, the absorptive-flux of cinnarizine and (3)H-oleic acid from mixed micelles decreased 6.5-fold and 3.0-fold, respectively. In contrast, the absorptive-flux of cinnarizine from Brij® 97 micelles remained unchanged by amiloride, and was significantly lower than from the long-chain micelles. Cinnarizine solubility in long-chain micelles decreased under conditions where pH and micellar lipid content decreased simultaneously.
  
  
  CONCLUSIONS
  The acidic microclimate of the intestinal UWL promotes drug absorption from intestinal mixed micelles via the promotion of fatty acid absorption which subsequently stimulates drug supersaturation. The observations suggest that formulations (or food) containing absorbable lipids (or their digestive precursors) may outperform formulations that lack absorbable components since the latter do not benefit from lipid absorption-induced drug supersaturation.
authors.affiliation: Drug Delivery, Disposition and Dynamics Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia.
authors.forename: Yan Yan
authors.initials: YY
authors.lastname: Yeap
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Trevaskis
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Porter
mesh_terms: D062646:Acid Sensing Ion Channel Blockers / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002936:Cinnarizine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003102:Colloids / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008823:Micelles; D019301:Oleic Acid / Q000378:metabolism*; D014677:Pharmaceutical Vehicles / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014867:Water / Q000378:metabolism
chemical_list: D062646:Acid Sensing Ion Channel Blockers; D002121:Calcium Channel Blockers; D003102:Colloids; D008823:Micelles; D014677:Pharmaceutical Vehicles; D014867:Water; D019301:Oleic Acid; D002936:Cinnarizine; D000584:Amiloride