title: Intraluminal drug and formulation behavior and integration in in vitro permeability estimation: a case study with amprenavir.
abstract: The purpose of this study was to assess the effect of biorelevant apical conditions on intestinal permeability estimation in the Caco-2 system for amprenavir, a poorly water-soluble substrate of the efflux carrier P-glycoprotein (P-gp). To establish biorelevant conditions, human intestinal fluids (HIF) were aspirated from the duodenum and jejunum in fasted subjects, before and during 4 h after the intake of a standard formulation of amprenavir (Agenerase). The HIF samples were characterized with respect to the concentrations of phospholipids, individual bile salts, amprenavir, and the excipient d-alpha-tocopheryl polyethyleneglycol 1000 succinate (TPGS); subsequently, the use of these samples in the Caco-2 system during permeability estimation for amprenavir was compared to standard conditions (amprenavir 10 microM dissolved in HBSS-based transport medium). The presence of the solubilizing excipient TPGS resulted in high intraluminal amprenavir concentrations (mM-range) and affected the permeability in a concentration-dependent way. At the observed intraluminal TPGS concentrations (mM-range), TPGS appeared to completely inhibit the interaction between amprenavir and P-gp, suggesting that the effect of P-gp on transepithelial transport of amprenavir in a clinical setting is probably negligible. This study illustrates the importance of the evaluation of intraluminal conditions after drug intake and their integration in permeability estimation in vitro.
authors.affiliation: Laboratory for Pharmacotechnology and Biopharmacy, Katholieke Universiteit Leuven, Belgium.
authors.forename: Joachim
authors.initials: J
authors.lastname: Brouwers
authors.forename: Jan
authors.initials: J
authors.lastname: Tack
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
mesh_terms: D000328:Adult; D018938:Caco-2 Cells; D002219:Carbamates / Q000737:chemistry / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D005079:Excipients; D005215:Fasting; D005260:Female; D005663:Furans; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D010539:Permeability / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D002219:Carbamates; D005079:Excipients; D005663:Furans; D004364:Pharmaceutical Preparations; D013449:Sulfonamides; C095108:amprenavir