Drug absorption limited by P-glycoprotein-mediated secretory drug transport in human intestinal epithelial Caco-2 cell layers.
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 microM; 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 microM). 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.
Hunter
J
J
Department of Physiological Sciences, Medical School, University of Newcastle upon Tyne, England.
Hirst
B H
BH
Simmons
N L
NL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins / Q000502:physiology*; D005576:Colforsin / Q000031:analogs & derivatives / Q000494:pharmacology; D000077143:Docetaxel; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000494:pharmacology; D043823:Taxoids; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D043823:Taxoids; D000077143:Docetaxel; D005576:Colforsin; D014747:Vinblastine; D014700:Verapamil; D009543:Nifedipine; C047983:1,9-dideoxyforskolin; D017239:Paclitaxel