title: Scaling of in vitro membrane permeability to predict P-glycoprotein-mediated drug absorption in vivo.
abstract: In a previous study, the concentration-dependent permeability of P-glycoprotein (P-gp) substrate drugs, quinidine, verapamil, and vinblastine, in several cell monolayers with different levels of P-gp expression was analyzed kinetically to obtain fundamental parameters for P-gp-mediated transport, V(max) and K(m(app)) values. Both V(max) and K(m(app)) values of each drug were found to show linear correlations with the expression level of P-gp. These findings imply the possibility of estimating the V(max) and K(m(app)) values of P-gp substrate drugs in the in vivo intestinal membrane on the basis of the P-gp expression level. In the present study, concentration-dependent drug permeability to the rat small intestines (upper jejunum and ileum) was simulated on the basis of V(max) and K(m(app)) values of each drug estimated from the P-gp expression level in the rat small intestines. To validate the predictability of these procedures, drug permeability in the rat small intestines was measured by the in situ single-pass perfusion method. It was confirmed that simulated permeability of each drug in the rat jejunum and ileum corresponded well with permeability measured by the in situ single-pass perfusion method. This study clearly demonstrated the potential to estimate the permeability of P-gp substrate drugs in the human intestine from its P-gp expression level and thus the possibility to predict the oral absorption of those drugs.
authors.affiliation: Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shirasaka
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Masaoka
authors.forename: Makoto
authors.initials: M
authors.lastname: Kataoka
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 / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002463:Cell Membrane Permeability; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism*; D008297:Male; D011802:Quinidine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014700:Verapamil / Q000378:metabolism; D014747:Vinblastine / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014747:Vinblastine; D014700:Verapamil; D011802:Quinidine