RT Journal Article
SR Electronic
T1 Variability in P-Glycoprotein Inhibitory Potency (IC_{50}) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug-Drug Interaction Risk Assessment Decision Criteria
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1347
OP 1366
DO 10.1124/dmd.112.050500
VO 41
IS 7
A1 Bentz, Joe
A1 O’Connor, Michael P.
A1 Bednarczyk, Dallas
A1 Coleman, JoAnn
A1 Lee, Caroline
A1 Palm, Johan
A1 Pak, Y. Anne
A1 Perloff, Elke S.
A1 Reyner, Eric
A1 Balimane, Praveen
A1 Brännström, Marie
A1 Chu, Xiaoyan
A1 Funk, Christoph
A1 Guo, Ailan
A1 Hanna, Imad
A1 Herédi-Szabó, Krisztina
A1 Hillgren, Kate
A1 Li, Libin
A1 Hollnack-Pusch, Evelyn
A1 Jamei, Masoud
A1 Lin, Xuena
A1 Mason, Andrew K.
A1 Neuhoff, Sibylle
A1 Patel, Aarti
A1 Podila, Lalitha
A1 Plise, Emile
A1 Rajaraman, Ganesh
A1 Salphati, Laurent
A1 Sands, Eric
A1 Taub, Mitchell E.
A1 Taur, Jan-Shiang
A1 Weitz, Dietmar
A1 Wortelboer, Heleen M.
A1 Xia, Cindy Q.
A1 Xiao, Guangqing
A1 Yabut, Jocelyn
A1 Yamagata, Tetsuo
A1 Zhang, Lei
A1 Ellens, Harma
YR 2013
UL http://dmd.aspetjournals.org/content/41/7/1347.abstract
AB 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.