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 i n the overall epithelial drug transfer which also involves distinct diffusi on processes in parallel and sequence. We used a simple three-compartment m odel to obtain kinetic parameters of each drug transfer mechanism, which ca n quantitatively describe the transport time courses of P-gp substrates, di goxin and vinblastine, across P-gp-expressing MDCK cell monolayers grown on permeable filters. Our results show that the model, which assumes a functi onally 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. Interes tingly, the model predicts that the MDCK apical membranes are less diffusio n permeable than the basolateral membrane for both drugs and that the distr ibution volume of vinblastine is 10-fold higher than that of digoxin. Addit ional experiments verified these model predictions. The modeling approach i s 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 ac counts for the pump function in this model awaits more studies.