If the KI is defined by the free energy of binding to P-gp, what kinetic parameters define the IC50 for the MDCKII-hMDR1 confluent cell monolayer? Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] Journal article | | Title | If the KI is defined by the free energy of binding to P-gp, what kinetic parameters define the IC50 for the MDCKII-hMDR1 confluent cell monolayer? | | Author(s) | Lumen AA, Acharya P, Polli JW, Ayrton A, Ellens H, Bentz J | | Institution | 1 Drexel University; | | Source | Drug Metab Dispos 2009 Nov 4. | | Abstract | From previous fits of drug transport kinetics across confluent MDCKII-hMDR1 cell monolayers, we found that a drug's binding constant to P-gp was significantly smaller than its IC50 when that drug was used as an inhibitor against another P-gp substrate. We tested several IC50 candidate functions, including the standard function, the Kalvass-Pollack function and the efflux ratio, to determine whether any of them yielded an IC50=K(I), as would be expected for water soluble enzymes. For the confluent cell monolayer, the IC50/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 IC50/K(I) ratio depends upon the elementary rate constants from our mass action model. Thus, the IC50 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 its ability to access the other transporters(if any) in the two cell lines. The mass action model and the approximate equation for the IC50/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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19889884 |
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