Lipid Absorption Triggers Drug Supersaturation at the Intestinal Unstirred Water Layer and Promotes Drug Absorption from Mixed Micelles

• Published in: Pharmaceutical research 2013-12, Vol.30 (12), p.3045-3058
• Main Authors: Yeap, Yan Yan, Trevaskis, Natalie L., Porter, Christopher J. H.
• Format: Article
• Language: English
• Subjects: Acid Sensing Ion Channel Blockers - pharmacology; Amiloride - pharmacology; Animals; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Calcium Channel Blockers - administration & dosage; Calcium Channel Blockers - pharmacokinetics; Cinnarizine - administration & dosage; Cinnarizine - pharmacokinetics; Colloids - metabolism; Digestive system; Intestinal Absorption - drug effects; Jejunum - drug effects; Jejunum - metabolism; Lipids; Male; Medical Law; Micelles; Oleic Acid - metabolism; Pharmaceutical sciences; Pharmaceutical Vehicles - metabolism; Pharmacology/Toxicology; Pharmacy; Rats; Rats, Sprague-Dawley; Research Paper; Rodents; Water - metabolism
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-013-1104-6

Purpose 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.