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If the KI is defined by the free energy of binding to P-glycoprotein, which kinetic parameters define the IC50 for the Madin-Darby canine kidney II cell line overexpressing human multidrug resistance 1 confluent cell monolayer?
- Source :
-
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2010 Feb; Vol. 38 (2), pp. 260-9. Date of Electronic Publication: 2009 Nov 04. - Publication Year :
- 2010
-
Abstract
- From previous fits of drug transport kinetics across confluent Madin-Darby canine kidney II cell line overexpressing human multidrug resistance 1 cell monolayers, we found that a drug's binding constant to P-glycoprotein (P-gp) was significantly smaller than its IC(50) when that drug was used as an inhibitor against another P-gp substrate. We tested several IC(50) candidate functions, including the standard function, the Kalvass-Pollack function, and the efflux ratio, to determine whether any of them yielded an IC(50) = K(I), as would be expected for water-soluble enzymes. For the confluent cell monolayer, the IC(50)/K(I) ratio is greater than 1 for all candidate functions tested. From the mass action kinetic model, we have derived a simple approximate equation that shows how the IC(50)/K(I) ratio depends on the elementary rate constants from our mass action model. Thus, the IC(50) will differ between cell lines and tissues, for the same probe substrate and inhibitor, if there are different membrane concentrations of P-gp, or the probe substrate's elementary rate constants, partition coefficient, binding constant to P-gp, passive permeability, and ability to access the other transporters (if any) in the two cell lines. The mass action model and the approximate equation for the IC(50)/K(I) ratio derived here can be used to estimate the elementary rate constants needed to extrapolate in vitro drug-drug interactions for compounds to the in vivo environment.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics
Animals
Biological Transport drug effects
Cell Line
Cell Membrane drug effects
Cell Membrane metabolism
Cell Membrane Permeability drug effects
Computer Simulation
Digoxin metabolism
Digoxin pharmacokinetics
Dogs
Drug Interactions
Genes, MDR
Humans
Kidney metabolism
Models, Biological
Protein Binding drug effects
Quinidine metabolism
Quinidine pharmacokinetics
Thermodynamics
ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1521-009X
- Volume :
- 38
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Drug metabolism and disposition: the biological fate of chemicals
- Publication Type :
- Academic Journal
- Accession number :
- 19889884
- Full Text :
- https://doi.org/10.1124/dmd.109.029843