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Vol. 303, Issue 3, 1095-1101, December 2002

Region-Dependent Modulation of Intestinal Permeability by Drug Efflux Transporters: In Vitro Studies in mdr1a(-/-) Mouse Intestine

R. H. Stephens, J. Tanianis-Hughes, N. B. Higgs, M. Humphrey and G. Warhurst

Gut Barrier Group, University of Manchester and Salford Hospitals Trust, Hope Hospital, Salford, (R.H.S., J.T.-H., N.B.H., G.W.), and Pharmaceutical Sciences, Pfizer Global Research & Development, Kent, United Kingdom (M.H.)

Information on the extent to which xenobiotics interact with P-glycoprotein (PGP) during transit through the intestine is crucial in determining the influence of PGP on oral drug absorption. We have recently described a novel use of isolated ileum from PGP-deficient mdr1a(-/-) mice to resolve PGP- and non-PGP-dependent drug efflux and provide a definitive measure of intrinsic drug permeability without recourse to inhibitors (Stephens et al., 2002). The present study uses this approach to investigate the impact of PGP on intestinal permeability of paclitaxel and digoxin in different regions of the mouse intestine (jejunum, ileum, and proximal and distal colon). Absorption of paclitaxel and digoxin in tissues from wild-type mice was low and showed little regional variation. In contrast, absorption of both drugs was markedly higher in mdr1a(-/-) intestine, although the increase was highly region-dependent, with the ileum and distal colon showing the greatest effect and much smaller changes in the jejunum and proximal colon. These effects were accompanied by the abolition of paclitaxel and digoxin secretion in mdr1a(-/-) mice, suggesting that regional variations in intestinal permeability are masked by differential PGP expression, confirmed by immunoblotting studies. Propranolol permeability, which is not influenced by PGP, showed similar regional variation in both wild-type and mdr1a(-/-) tissues, suggesting that differences are at the level of transcellular permeability. These data suggest that the ileum and the distal colon are regions of relatively high transcellular permeability for xenobiotics that are compensated by enhanced expression of PGP.

0022-3565/02/3033-1095$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics.