Prediction of in vivo intestinal absorption enhancement on P-glycoprotein inhibition, from rat in situ permeability

J Pharm Sci. 2005 Aug;94(8):1694-704. doi: 10.1002/jps.20309.


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.

Publication types

  • Comparative Study

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Cyclosporine / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Ileum / drug effects*
  • Ileum / metabolism
  • Intestinal Absorption / drug effects*
  • Models, Biological
  • Perfusion
  • Permeability / drug effects
  • Predictive Value of Tests
  • Quinidine / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Solubility / drug effects


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cyclosporine
  • Quinidine