Journal article
Derivation of a System-Independent K-i for P-glycoprotein Mediated Digoxin Transport from System-Dependent IC50 Data
Drug metabolism and disposition, v 46(3), pp 279-290
01 Mar 2018
PMID: 29317410
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
It has been previously demonstrated that IC50 values for inhibition of digoxin transport across confluent polarized cell monolayers are system-dependent. Digoxin IC50 data from five laboratories participating in the P-glycoprotein (P-gp) IC50 Initiative, using Caco-2, MDCKII-hMDR1 or LLC-PK1-hMDR1 cells, were fitted by the structural mass action kinetic model for P-gp-mediated transport across confluent cell monolayers. We determined their efflux-active P-gp concentration [T(0)], inhibitor elementary dissociation rate constant from P-gp (k(rQ)), digoxin basolateral uptake clearance (k(B)), and inhibitor binding affinity to the digoxin basolateral uptake transporter (K-QB). We also fitted the IC50 data for inhibition of digoxin transport through monolayers of primary human proximal tubule cells (HPTCs). All cell systems kinetically required a basolateral uptake transporter for digoxin, which also bound to all inhibitors. The inhibitor k(rQ) was cell system-independent, thereby allowing calculation of a system-independent Ki. The variability in efflux-active P-gp concentrations and basolateral uptake clearances in the five laboratories was about an order of magnitude. These laboratory-to-laboratory variabilities can explain more than 60% of the IC50 variability found in the principal component analysis plot in a previous study, supporting the hypothesis that the observed IC50 variability is primarily due to differences in expression levels of efflux-active P-gp and the basolateral digoxin uptake transporter. HPTCs had 10- to 100-fold lower efflux-active P-gp concentrations than the overexpressing cell lines, whereas their digoxin basolateral uptake clearances were similar. HPTC basolateral uptake of digoxin was inhibited 50% by 10 mu M ouabain, suggesting involvement of OATP4C1.
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Details
- Title
- Derivation of a System-Independent K-i for P-glycoprotein Mediated Digoxin Transport from System-Dependent IC50 Data
- Creators
- Aqsaa Chaudhry - Newcastle UniversityGit Chung - Newcastle UniversityAdam Lynn - Newcastle UniversityAkshata Yalvigi - Newcastle UniversityColin Brown - Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne, Tyne & Wear, EnglandHarma Ellens - Newcastle UniversityMichael O'Connor - University of Newcastle AustraliaCaroline Lee - Newcastle UniversityJoe Bentz - Drexel University
- Publication Details
- Drug metabolism and disposition, v 46(3), pp 279-290
- Publisher
- Amer Soc Pharmacology Experimental Therapeutics
- Number of pages
- 12
- Grant note
- NC/C013112/1 / National Centre for the Replacement BBSRC- AstraZeneca CASE studentship
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology; [Retired Faculty]
- Web of Science ID
- WOS:000426966000009
- Scopus ID
- 2-s2.0-85042183976
- Other Identifier
- 991019168046204721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Pharmacology & Pharmacy