Modeling of P-glycoprotein-involved epithelial drug transport in MDCK cells.
P-glycoprotein (P-gp) on the apical membranes of epithelial cells is known as a drug efflux pump. However, unclear is its integral quantitative role in the overall epithelial drug transfer, which also involves distinct diffusion processes in parallel and sequence. We used a simple three-compartment model to obtain kinetic parameters of each drug transfer mechanism, which can quantitatively describe the transport time courses of P-gp substrates, digoxin and vinblastine, across P-gp-expressing MDCK cell monolayers grown on permeable filters. Our results show that the model, which assumes a functionally single drug efflux pump in the apical membrane with diffusion across two membranes and intercellular junctions, is the least complex model with which to quantitatively reproduce the characteristics of the data. Interestingly, the model predicts that the MDCK apical membranes are less diffusion permeable than the basolateral membrane for both drugs and that the distribution volume of vinblastine is 10-fold higher than that of digoxin. Additional experiments verified these model predictions. The modeling approach is feasible to quantitatively describe overall kinetic picture of epithelial drug transport. Further model refinement is necessary to incorporate other modes of drug transport such as transcytosis. Also, whether P-gp solely accounts for the pump function in this model awaits more studies.
Division of Clinical Pharmacology and Toxicology, Departments of Pediatrics and Pharmacology, Hospital for Sick Children, Research Institute, University of Toronto, Canada.
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Woodland
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Sarkadi
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Hockmann
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Walker
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Koren
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000378:metabolism; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004077:Digoxin / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D005452:Fluoresceins / Q000378:metabolism; D015151:Immunoblotting; D008353:Mannitol / Q000378:metabolism; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014747:Vinblastine / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D004077:Digoxin; D005452:Fluoresceins; D008353:Mannitol; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014747:Vinblastine; C007740:fluorexon