RT Journal Article
SR Electronic
T1 Scaling of in Vitro Membrane Permeability to Predict P-glycoprotein-Mediated Drug Absorption in Vivo
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 916
OP 922
DO 10.1124/dmd.107.020040
VO 36
IS 5
A1 Yoshiyuki Shirasaka
A1 Yoshie Masaoka
A1 Makoto Kataoka
A1 Shinji Sakuma
A1 Shinji Yamashita
YR 2008
UL http://dmd.aspetjournals.org/content/36/5/916.abstract
AB 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, Vmax and Km(app) values. Both Vmax and Km(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 Vmax and Km(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 Vmax and Km(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. The American Society for Pharmacology and Experimental Therapeutics