Model analysis of the concentration-dependent permeability of P-gp substrates

Pharm Res. 2010 Mar;27(3):442-6. doi: 10.1007/s11095-009-0026-9. Epub 2010 Feb 5.


Purpose: Recently, it was reported that the apparent Michaelis-Menten constant (Km(app)) of a P-glycoprotein (P-gp) substrate, defined for the extracellular substrate concentration, increases as the P-gp expression level in the cell increases. By its nature, the Km value should not depend on the level of P-gp expression. The purpose of this study is to establish a model which can estimate the Km value independent of the P-gp expression level in cells.

Methods: The previously reported concentration-dependent permeability of verapamil, quinidine, and vinblastine in MDR1-MDCKII, P-gp-highly induced Caco-2, P-gp-induced Caco-2, normal Caco-2, and MDR1-knockdown Caco-2 cells data were analyzed using a model in which the Km value was defined for the intracellular substrate concentration.

Results: The estimated Km values defined for the substrate concentration inside the cells were almost the same among various cells with different levels of P-gp expression. The estimated Vmax values were approximately proportional to the P-gp expression level.

Conclusion: The established kinetic model was found to be rational based on the results that the Km values of P-gp substrates were about the same for cells expressing various levels of P-gp, while the Vmax values were proportional to the expression levels of P-gp.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Biological Transport
  • Caco-2 Cells
  • Gene Expression
  • Humans
  • Models, Biological
  • Quinidine / pharmacokinetics*
  • Verapamil / pharmacokinetics*
  • Vinblastine / pharmacokinetics*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Vinblastine
  • Verapamil
  • Quinidine