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J Pharm Sci. 2005 Aug;94(8):1694-704.

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

Author information

1
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Phase X, SAS. Nagar, Punjab 160062, India.

Abstract

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.

PMID:
15986467
DOI:
10.1002/jps.20309
[Indexed for MEDLINE]

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