title: Permeation characteristics of a hydrophilic basic compound across a bio-mimetic artificial membrane.
abstract: In the present study, the permeation characteristics of a hydrophilic basic compound (HBC) in a bio-mimetic parallel artificial membrane permeability assay (bio-mimetic PAMPA) were investigated in detail. The bio-mimetic PAMPA membrane was constructed on a hydrophobic filter by impregnating a lipid solution consisting of phosphatidylcholine (0.8%, w/w), phosphatidylethanolamine (0.8%, w/w), phosphatidylserine (0.2%, w/w), phosphatidylinositol (0.2%, w/w), cholesterol (1.0%, w/w), and 1,7-octadiene (97.0%, w/w). The pH-permeability curve (pH 3-10), the effect of lipid composition, concentration dependency (0.02-2.00 mM), and inhibition by other cationic compounds, were investigated for several HBCs. Ketoprofen and methylchlorpromazine were also employed as an acidic and a quaternary ammonium compound, respectively. At pH 3-6, the permeability of timolol, a HBC, was higher than expected from the pH-partition hypothesis, especially in the PI-containing membrane, whereas the pH-permeability curve of ketoprofen followed the pH-partition hypothesis. Permeation of HBC was saturable and inhibited by basic and quaternary ammonium compounds. Similar results were also found for methylchlorpromazine. The permeation characteristics of HBC observed in the present study are not usually expected in a passive permeation process across an artificial membrane. The participation of facilitated permeation of cationic species was suggested, in addition to a simple passive diffusion of un-dissociated species. Ion pair transport was suggested as a possible permeation mechanism of cationic species. However, further investigation is necessary to clarify the reason for the permeation characteristics of HBC.
authors.affiliation: Pre-clinical Research Department I, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. suganokyh@chugai-pharm.co.jp
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Sugano
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Nabuchi
authors.forename: Minoru
authors.initials: M
authors.lastname: Machida
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Asoh
mesh_terms: D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D002746:Chlorpromazine / Q000031:analogs & derivatives* / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008567:Membranes, Artificial; D009823:Ointment Bases / Q000737:chemistry*; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010743:Phospholipids / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000737:chemistry
chemical_list: D008567:Membranes, Artificial; D009823:Ointment Bases; D004364:Pharmaceutical Preparations; D010743:Phospholipids; D000644:Quaternary Ammonium Compounds; C008392:methochlorpromazine; D002746:Chlorpromazine