Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug-Drug Interaction Risk Assessment Decision Criteria
| Autor: | Laurent Salphati, Eric Sands, Praveen Balimane, Caroline A. Lee, Johan E. Palm, Joe Bentz, Lalitha Podila, Jesse Taur, Tetsuo Yamagata, Lei K. Zhang, Kathleen M. Hillgren, Eric L. Reyner, Marie Brännström, Dietmar Weitz, Emile Plise, Jocelyn Yabut, Masoud Jamei, Harma Ellens, Anne Pak, Dallas Bednarczyk, Guangqing Xiao, Mitchell E. Taub, Libin Li, Heleen M. Wortelboer, Elke S Perloff, Andrew K Mason, Michael P. O'Connor, Krisztina Herédi-Szabó, Aarti Patel, Ganesh Rajaraman, Xiaoyan Chu, Evelyn Hollnack-Pusch, Christoph Funk, Joann Coleman, Cindy Q. Xia, Xuena Lin, Imad Hanna, Ailan Guo, Sibylle Neuhoff |
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| Rok vydání: | 2013 |
| Předmět: |
Digoxin
Swine Pharmaceutical Science Pharmacology Risk Assessment Inhibitory Concentration 50 Dogs medicine Animals Humans Drug Interactions ATP Binding Cassette Transporter Subfamily B Member 1 IC50 P-glycoprotein Principal Component Analysis Isradipine biology Chemistry Biological Transport Articles In vitro biology.protein LLC-PK1 Cells Verapamil Efflux Caco-2 Cells Telmisartan medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 41:1347-1366 |
| ISSN: | 1521-009X 0090-9556 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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