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Journal article
Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug-Drug Interaction Risk Assessment Decision Criteria
Drug metabolism and disposition, v 41(7), pp 1347-1366
01 Jul 2013
PMCID: PMC3684820
PMID: 23620485
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
A P-glycoprotein (P-gp) IC50 working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC50 determinations. Each laboratory followed its in-house protocol to determine in vitro IC50 values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells-Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e. g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC50 values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC50 values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC50 values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in several fold lower IC50 values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC50 values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC50 determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens et al., 2013) and recommendations are provided.
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Details
- Title
- Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug-Drug Interaction Risk Assessment Decision Criteria
- Creators
- Joe Bentz - Drexel UniversityMichael P. O'Connor - Drexel UniversityDallas Bednarczyk - Optivia BiotechnologyJoAnn Coleman - GlaxoSmithKline Pharmaceuticals LtdCaroline Lee - DMPK Solutions, Inc;Johan Palm - AstraZeneca R&D, Saffron Walden, United Kingdom;Y. Anne Pak - Eli Lilly & Co, Lilly Res Labs, Investigat Drug Disposit, Indianapolis, IN 46285 USAElke S. Perloff - BD BiosciencesEric Reyner - Pfizer,Praveen Balimane - Bristol-Myers SquibbMarie Brannstrom - AstraZenecaXiaoyan Chu - Merck & CoChristoph Funk - RocheAilan Guo - RocheImad Hanna - NovartisKrisztina Heredi-Szabo - Solvo BiotechnologyKate Hillgren - Eli Lilly & Co, Lilly Res Labs, Investigat Drug Disposit, Indianapolis, IN 46285 USALibin Li - Absorption SystemsEvelyn Hollnack-Pusch - RocheMasoud Jamei - SimcypXuena Lin - NovartisAndrew K. Mason - BD BiosciencesSibylle Neuhoff - SimcypAarti Patel - GlaxoSmithKline Pharmaceuticals LtdLalitha Podila - Boehringer IngelheimEmile Plise - GenentechGanesh Rajaraman - Thermo Fisher ScientificLaurent Salphati - GenentechEric Sands - BiogenMitchell E. Taub - Boehringer Ingelheim Pharmaceuticals, Inc.Jan-Shiang Taur - Eisai Inc, Andover, MA USADietmar Weitz - SanofiHeleen M. Wortelboer - TNO > > > >Cindy Q. Xia - Millennium PharmaceuticalsGuangqing Xiao - BiogenJocelyn Yabut - Merck & CoTetsuo Yamagata - Merck SeronoLei Zhang - Center for Drug Evaluation and ResearchHarma Ellens - GlaxoSmithKline Pharmaceuticals Ltd
- Publication Details
- Drug metabolism and disposition, v 41(7), pp 1347-1366
- Publisher
- Amer Soc Pharmacology Experimental Therapeutics
- Number of pages
- 20
- Grant note
- R43GM086970 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R43GM086970-01; R43RR031474-01 / Small Business Innovation Research Grants from the National Institutes of Health National Institute of General Medical Sciences R43RR031474 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biodiversity, Earth, and Environmental Science (BEES); Biology; [Retired Faculty]
- Web of Science ID
- WOS:000320307100007
- Scopus ID
- 2-s2.0-84879085257
- Other Identifier
- 991019168150004721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Pharmacology & Pharmacy