Prediction of in vivo intestinal absorption enhancement on P-glycoprotein inhibition, from rat in situ permeability.
The purpose of this study is to determine the functional role of P-glycoprotein (P-gp) in intestinal absorption of drugs and to quantitatively predict the in vivo absorption enhancement on P-gp inhibition. In situ single-pass rat ileum permeability and aqueous solubility were measured for a set of 16 compounds. Permeability studies were also carried out in the presence of P-gp inhibitor to estimate the permeability enhancement on P-gp inhibition. A significant correlation was obtained between rat ileum permeability and the literature human intestinal absorption (HIA), F(a,human) (r = 0.891; p < 0.01). Compounds with permeability >0.2 x 10(-4) cm/s are completely absorbed; however, few practically insoluble compounds were overestimated with this relationship. Inhibition of P-gp increased the permeability (p < 0.05) of three moderately and three highly permeable compounds. Efflux inhibition ratio (EIR), the ratio of permeability due to P-gp-mediated efflux activity and passive permeability only, for these compounds was in the order of digoxin > paclitaxel > fexofenadine > quinidine > verapamil > cyclosporine. Integration of EIR with permeability versus F(a,human) predicted that modulation of P-gp has no significant effect on the absorption of highly permeable compounds (quinidine, verapamil, and cyclosporine A), while for moderately permeable compounds (digoxin, paclitaxel, and fexofenadine), P-gp profoundly influences the intestinal permeability. The in situ permeability in rat ileum may be used to predict the in vivo P-gp function and its quantitative contribution to intestinal drug absorption. Integration of the functional activity of P-gp with the characteristics of BCS may explain drug interactions and explore the possible pharmacokinetic advantage on P-gp inhibition.
Varma
Manthena V S
MV
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Phase X, SAS. Nagar, Punjab 160062, India.
Panchagnula
Ramesh
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects*; D008954:Models, Biological; D010477:Perfusion; D010539:Permeability / Q000187:drug effects; D011237:Predictive Value of Tests; D011802:Quinidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016572:Cyclosporine; D011802:Quinidine