Modeling of P-glycoprotein-involved epithelial drug transport in MDCK cells

Shinya Ito, Cindy Woodland, B. Sarkadi, Guido Hockmann, Scott E. Walker, Gideon Koren

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalAmerican Journal of Physiology - Renal Physiology
Volume277
Issue number1 46-1
Publication statusPublished - Jul 1999

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Madin Darby Canine Kidney Cells
P-Glycoprotein
Pharmaceutical Preparations
Membranes
Vinblastine
Digoxin
Transcytosis
Intercellular Junctions
Epithelial Cells

Keywords

  • Diffusion
  • Itraconazole
  • Multidrug resistance
  • P-glycoprotein

ASJC Scopus subject areas

  • Physiology

Cite this

Modeling of P-glycoprotein-involved epithelial drug transport in MDCK cells. / Ito, Shinya; Woodland, Cindy; Sarkadi, B.; Hockmann, Guido; Walker, Scott E.; Koren, Gideon.

In: American Journal of Physiology - Renal Physiology, Vol. 277, No. 1 46-1, 07.1999.

Research output: Contribution to journalArticle

Ito, Shinya ; Woodland, Cindy ; Sarkadi, B. ; Hockmann, Guido ; Walker, Scott E. ; Koren, Gideon. / Modeling of P-glycoprotein-involved epithelial drug transport in MDCK cells. In: American Journal of Physiology - Renal Physiology. 1999 ; Vol. 277, No. 1 46-1.
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