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.
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.
Authors: Kiyohiko Sugano; Manfred Kansy; Per Artursson; Alex Avdeef; Stefanie Bendels; Li Di; Gerhard F Ecker; Bernard Faller; Holger Fischer; Grégori Gerebtzoff; Hans Lennernaes; Frank Senner Journal: Nat Rev Drug Discov Date: 2010-08 Impact factor: 84.694
Authors: X Chu; K Korzekwa; R Elsby; K Fenner; A Galetin; Y Lai; P Matsson; A Moss; S Nagar; G R Rosania; J P F Bai; J W Polli; Y Sugiyama; K L R Brouwer Journal: Clin Pharmacol Ther Date: 2013-04-10 Impact factor: 6.875
Authors: M J Zamek-Gliszczynski; C A Lee; A Poirier; J Bentz; X Chu; H Ellens; T Ishikawa; M Jamei; J C Kalvass; S Nagar; K S Pang; K Korzekwa; P W Swaan; M E Taub; P Zhao; A Galetin Journal: Clin Pharmacol Ther Date: 2013-02-25 Impact factor: 6.875
Authors: Alice Ban Ke; Sara Eyal; Francisco S Chung; Jeanne M Link; David A Mankoff; Mark Muzi; Jashvant D Unadkat Journal: J Nucl Med Date: 2013-01-28 Impact factor: 10.057