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Variability inP-GlycoproteinInhibitory Potency(IC50) Using Variousin Vitro ExperimentalSystems Joe BentzMichael O’ConnorDallas Bednarczyk2013 год

Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug-Drug Interaction Risk Assessment Decision Criteria
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Аннотация: 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 severalfold 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.
Год издания: 2013
Авторы: Joe Bentz, Michael O’Connor, Dallas Bednarczyk, JoAnn Coleman, Caroline Lee, Johan Palm, Y. Anne Pak, Elke S. Perloff, Eric L. Reyner, Praveen Balimane, Marie Brännström, Xiaoyan Chu, Christoph Funk, Ailan Guo, Imad Hanna, Krisztina Herédi‐Szabó, Kate Hillgren, Libin Li, Evelyn Hollnack-Pusch, Masoud Jamei, Xuena Lin, Andrew K. Mason, Sibylle Neuhoff, Aarti Patel, Lalitha Podila, Emile G. Plise, Ganesh Rajaraman, Laurent Salphati, Eric Sands, Mitchell E. Taub, Jan-Shiang Taur, Dietmar Weitz, Heleen M. Wortelboer, Cindy Q. Xia, Guangqing Xiao, Jocelyn Yabut, Tetsuo Yamagata, Lei Zhang, Harma Ellens
Издательство: American Society for Pharmacology and Experimental Therapeutics
Источник: Drug Metabolism and Disposition
Ключевые слова: Drug Transport and Resistance Mechanisms, Pharmacological Effects and Toxicity Studies, Pharmacogenetics and Drug Metabolism
Другие ссылки: Drug Metabolism and Disposition (HTML)
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