Pharmaceutical Research

, Volume 10, Issue 5, pp 743–749 | Cite as

Drug Absorption Limited by P-Glycoprotein-Mediated Secretory Drug Transport in Human Intestinal Epithelial Caco-2 Cell Layers

  • Janice Hunter
  • Barry H. Hirst
  • Nicholas L. Simmons


The hypothesis was tested that the operation of an ATP-dependent export pump localized at the apical (brush border) surface of the intestinal epithelium may limit substrate absorption kinetics. Human intestinal Caco-2 cell-layers display saturable secretion of vinblastine from basal to apical surfaces (Km, 18.99 ± 5.55 µM; Vmax, 1285.9 ± 281.2 pmol cm−2 hr−1) that is inhibited by verapamil, consistent with the expression of the ATP-dependent P-glycoprotein drug efflux pump at the apical brush border membrane. Inhibition of P-glycoprotein by a variety of modulators (verapamil, 1,9-dideoxyforskolin, nifedipine, and taxotere) is associated with an increased vinblastine absorptive permeability. Vinblastine absorption displayed a nonlinear dependence upon luminal (apical) vinblastine concentration, and vinblastine absorption increased markedly at concentrations where vinblastine secretory flux was saturated (>20 µM). Upon inhibition of P-glycoprotein by verapamil and 1,9-dideoxyforskolin, vinblastine absorption increased and was linearly dependent on vinblastine concentration. The limitation of P-glycoprotein substrate absorption by active ATP-dependent export via P-glycoprotein is discussed, together with the possibility that other classes of substrate may be substrates for different ATP-dependent export pumps.

absorption limitation Caco-2 cells P-glycoprotein multidrug resistance intestine oral drug delivery vinblastine verapamil 


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Copyright information

© Plenum Publishing Corporation 1993

Authors and Affiliations

  • Janice Hunter
    • 1
  • Barry H. Hirst
    • 1
  • Nicholas L. Simmons
    • 1
  1. 1.Gastrointestinal Drug Delivery Research Centre, Department of Physiological Sciences, Medical SchoolUniversity of Newcastle upon TyneEngland

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