Journal article
Mechanistic kinetic modeling generates system-independent P-glycoprotein mediated transport elementary rate constants for inhibition and, in combination with 3D SIM microscopy, elucidates the importance of microvilli morphology on P-glycoprotein mediated efflux activity
Expert opinion on drug metabolism & toxicology, v 14(6), pp 571-584
01 Jan 2018
PMID: 29788828
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Introduction: In vitro transporter kinetics are typically analyzed by steady-state Michaelis-Menten approximations. However, no clear evidence exists that these approximations, applied to multiple transporters in biological membranes, yield system-independent mechanistic parameters needed for reliable in vivo hypothesis generation and testing.
Areas covered: The classical mass action model has been developed for P-glycoprotein (P-gp) mediated transport across confluent polarized cell monolayers. Numerical integration of the mass action equations for transport using a stable global optimization program yields fitted elementary rate constants that are system-independent. The efflux active P-gp was defined by the rate at which P-gp delivers drugs to the apical chamber, since as much as 90% of drugs effluxed by P-gp partition back into nearby microvilli prior to reaching the apical chamber. The efflux active P-gp concentration was 10-fold smaller than the total expressed P-gp for Caco-2 cells, due to their microvilli membrane morphology. The mechanistic insights from this analysis are readily extrapolated to P-gp mediated transport in vivo.
Expert opinion: In vitro system-independent elementary rate constants for transporters are essential for the generation and validation of robust mechanistic PBPK models. Our modeling approach and programs have broad application potential. They can be used for any drug transporter with minor adaptations.
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Details
- Title
- Mechanistic kinetic modeling generates system-independent P-glycoprotein mediated transport elementary rate constants for inhibition and, in combination with 3D SIM microscopy, elucidates the importance of microvilli morphology on P-glycoprotein mediated efflux activity
- Creators
- Harma Ellens - Drexel UniversityZhou Meng - Drexel UniversitySylvain J. Le Marchand - Drexel UniversityJoe Bentz - Drexel University
- Publication Details
- Expert opinion on drug metabolism & toxicology, v 14(6), pp 571-584
- Publisher
- Taylor & Francis
- Number of pages
- 14
- Grant note
- 140136-3650-4999 / Drexel University Fund PI O/H Share J. Bentz Department of Biology (Drexel University)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000435331500003
- Scopus ID
- 2-s2.0-85048667116
- Other Identifier
- 991019169814504721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Biochemistry & Molecular Biology
- Pharmacology & Pharmacy
- Toxicology