Journal article
Extrapolation of Elementary Rate Constants of P-glycoprotein-Mediated Transport from MDCKII-hMDR1-NKI to Caco-2 Cells
Drug metabolism and disposition, v 45(2), pp 190-197
Feb 2017
PMID: 27856526
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The best parameters for incorporation into mechanistic physiologically based pharmacokinetic models for transporters are system-independent kinetic parameters and active (not total) transporter levels. Previously, we determined the elementary rate constants for P-glycoprotein (P-gp)-mediated transport (on- and off-rate constants from membrane to P-gp binding pocket and efflux rate constant into the apical chamber) using the structural mass action kinetic model in confluent MDCKII-hMDR1-NKI cell monolayers. In the present work, we extended the kinetic analysis to Caco-2 cells for the first time and showed that the elementary rate constants are very similar compared with MDCKII-hMDR1-NKI cells, suggesting they primarily depend on the interaction of the compound with P-gp and are therefore mostly independent of the in vitro system used. The level of efflux active (not total) P-gp is also fitted by our model. The estimated level of efflux active P-gp was 5.0 ± 1.4-fold lower in Caco-2 cells than in MDCKII-hMDR1-NKI cells. We also kinetically identified the involvement of a basolateral uptake transporter for both digoxin and loperamide in Caco-2 cells, as found previously in MDCKII-hMDR1-NKI cells, due to their low passive permeability. This demonstrates the value of our P-gp structural model as a diagnostic tool in detecting the importance of other transporters, which cannot be unambiguously done by the Michaelis-Menten approach. The system-independent elementary rate constants for P-gp obtained in vitro are more fundamental parameters than those obtained using Michaelis-Menten steady-state equations. This suggests they will be more robust mechanistic parameters for incorporation into physiologically based pharmacokinetic models for transporters.
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Details
- Title
- Extrapolation of Elementary Rate Constants of P-glycoprotein-Mediated Transport from MDCKII-hMDR1-NKI to Caco-2 Cells
- Creators
- Zhou Meng - Drexel University, Department of Biology, Philadelphia, Pennsylvania (Z.M., J.B.); and GlaxoSmithKline Pharmaceuticals, Drug Metabolism and Pharmacokinetics, King of Prussia, Pennsylvania (Z.M., H.E.).Harma Ellens - Drexel University, Department of Biology, Philadelphia, Pennsylvania (Z.M., J.B.); and GlaxoSmithKline Pharmaceuticals, Drug Metabolism and Pharmacokinetics, King of Prussia, Pennsylvania (Z.M., H.E.).Joe Bentz - Drexel University, Department of Biology, Philadelphia, Pennsylvania (Z.M., J.B.); and GlaxoSmithKline Pharmaceuticals, Drug Metabolism and Pharmacokinetics, King of Prussia, Pennsylvania (Z.M., H.E.).
- Publication Details
- Drug metabolism and disposition, v 45(2), pp 190-197
- Publisher
- American Society for Pharmacology and Experimental Therapeutics (ASPET)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000393203400010
- Scopus ID
- 2-s2.0-85010976353
- Other Identifier
- 991019169692804721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Pharmacology & Pharmacy