title: Estimation of P-glycoprotein-mediated efflux in the oral absorption of P-gp substrate drugs from simultaneous analysis of drug dissolution and permeation.
abstract: The purpose of this study was to establish an in vitro system that evaluates the effects of P-glycoprotein (P-gp)-mediated efflux on the oral absorption of P-gp substrates. An in vitro system (dissolution/permeation system, D/P system) was developed that consisted of apical and basal chambers and a Caco-2 cell monolayer mounted between the chambers. Both sides of the monolayer were filled with physiological solution and were stirred at 200rpm. The dissolution in the apical medium and permeation to the basal medium were monitored for 2h after P-gp substrates were applied to the apical side of the system. When erythromycin existed in the apical medium, the permeations of fexofenadine and talinolol were significantly enhanced without change in their dissolution. The prediction of oral absorptions of fexofenadine and talinolol from in vitro data indicated that co-administration of erythromycin results in 2.1- and 1.9-fold higher oral absorptions, respectively. Moreover, the D/P system could estimate the effect of cremophor EL on the oral absorption of saquinavir. These estimations corresponded well to in vivo human observations. Our in vitro system is useful in assessment of the effect of P-gp-mediated efflux on in vivo oral absorption of P-gp substrates.
authors.affiliation: Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, Japan. makoto@pharm.setsunan.ac.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Kataoka
authors.forename: Tomonori
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Masaoka
authors.forename: Shinji
authors.initials: S
authors.lastname: Sakuma
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000465:Algorithms; D018938:Caco-2 Cells; D004347:Drug Interactions / Q000502:physiology; D004917:Erythromycin / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005990:Glycerol / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D008139:Loperamide / Q000378:metabolism; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011412:Propanolamines / Q000378:metabolism; D011691:Puromycin / Q000494:pharmacology; D011802:Quinidine / Q000378:metabolism; D019258:Saquinavir / Q000378:metabolism; D012995:Solubility; D013501:Surface-Active Agents / Q000494:pharmacology; D016593:Terfenadine / Q000031:analogs & derivatives / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations; D011412:Propanolamines; D013501:Surface-Active Agents; C011550:talinolol; D011691:Puromycin; D014747:Vinblastine; D004917:Erythromycin; C000515:cremophor EL; D008139:Loperamide; D016593:Terfenadine; D014700:Verapamil; C093230:fexofenadine; D011802:Quinidine; D019258:Saquinavir; D005990:Glycerol