Article Title: Application of Receiver Operating Characteristic (ROC) Analysis to Refine the Prediction of Potential Digoxin

Drug Interactions

Authors: Harma Ellens, Shibing Deng, JoAnn. Coleman, Joe Bentz, Mitchell E.Taub, Isabelle Ragueneau-Majlessi, Sophie P.Chung,

Krisztina Herédi-Szabó, Sibylle Neuhoff, Johan Palm, Praveen Balimane, Lei Zhang, Masoud Jamei, Imad Hanna, Michael O’Connor,

Dallas Bednarczyk, Malin Forsgard, Xiaoyan Chu, Christoph Funk, Ailan.Guo, Kathleen Hillgren, LiBin Li, Anne Y. Pak, Elke S.

Perloff, Ganesh G. Rajaraman, Laurent Salphati, Jesse Taur, Dietmar Weitz, Heleen M. Wortelboer, Cindy Q. Xia, Guangqing Xao,

Tetsuo Yamagata and Caroline.A. Lee

Journal Title: Drug Metabolism and Disposition

Supplemental Table 1. In vitro IC50 values determined by individual laboratories.

System Inhibitor IC50 (µM) System Inhibitor IC50 (µM) System Inhibitor IC50 (µM)

Caco Amiodarone 6.1 Caco isradipine 8.8 Caco Nifedipine 48.2

Caco carvedilol 0.7 Caco isradipine 2.6 Caco Nifedipine 95.1

Caco carvedilol 2.6 Caco isradipine 4.9 Caco Nifedipine 4.1

Caco carvedilol 1.4 Caco isradipine 10.6 Caco Nifedipine 129.7

Caco carvedilol 3.0 Caco isradipine 8.0 Caco Nifedipine 155.3

Caco carvedilol 9.5 Caco isradipine 59.5 Caco Nitrendipine 15.8

Caco carvedilol 0.9 Caco isradipine 34.2 Caco Nitrendipine 10.5

Caco carvedilol 15.1 Caco mibefradil 1.3 Caco Nitrendipine 28.1

Caco carvedilol 16.0 Caco mibefradil 29.8 Caco Nitrendipine 2.5

Caco diltiazem 8.3 Caco mibefradil 2.5 Caco Nitrendipine 8.9

Caco diltiazem 22.7 Caco mibefradil 11.3 Caco Nitrendipine 22.0

Caco diltiazem 5.7 Caco mibefradil 1.7 Caco quinidine 5.1

Caco diltiazem 5.0 Caco mibefradil 13.4 Caco quinidine 2.3

Caco diltiazem 22.9 Caco mibefradil 7.6 Caco quinidine 6.4

Caco diltiazem 71.2 Caco mibefradil 13.1 Caco quinidine 2.3

Caco diltiazem 71.9 Caco mibefradil 12.8 Caco quinidine 5.5

Caco diltiazem 154.6 Caco nicardipine 1.0 Caco quinidine 6.8

Caco Felodipine 4.7 Caco nicardipine 1.8 Caco quinidine 17.2

Caco Felodipine 14.1 Caco nicardipine 0.8 Caco quinidine 34.6

Caco Felodipine 29.4 Caco nicardipine 4.3 Caco quinidine 13.1

Caco Felodipine 56.4 Caco nicardipine 20.4 Caco ranolazine 15.0

Caco Felodipine 4.4 Caco nicardipine 6.7 Caco ranolazine 9.8

Caco Felodipine 8.0 Caco nicardipine 4.2 Caco ranolazine 15.2

Caco Felodipine 54.8 Caco Nifedipine 69.0 Caco ranolazine 16.3

Caco isradipine 7.0 Caco Nifedipine 38.2 Caco ranolazine 21.4

Caco isradipine 7.2 Caco Nifedipine 59.1 LLCPK verapamil 8.5

Caco ranolazine 62.0 Caco verapamil 1.8 LLCPK verapamil 34.9

Caco ranolazine 72.5 Caco verapamil 7.0 LLCPK verapamil 8.6

Caco Sertraline 37.5 Caco verapamil 1.5 MDCK Amiodarone 17.1

Caco Sertraline 37.3 Caco verapamil 1.3 MDCK Amiodarone 32.8

Caco Sertraline 7.4 Caco verapamil 2.9 MDCK Amiodarone 28.1

Caco Sertraline 32.9 Caco verapamil 4.6 MDCK Amiodarone 44.5

Caco Sertraline 127.9 Caco verapamil 5.6 MDCK Amiodarone 11.8

Caco Telmisartan 1.0 Caco verapamil 0.5 MDCK carvedilol 3.6

Caco Telmisartan 7.6 Caco verapamil 18.6 MDCK carvedilol 6.8

Caco Telmisartan 6.3 Caco verapamil 24.9 MDCK carvedilol 9.4

Caco Telmisartan 1.2 LLCPK Amiodarone 11.8 MDCK carvedilol 8.1

Caco Telmisartan 4.3 LLCPK Amiodarone 18.9 MDCK carvedilol 2.3

Caco Telmisartan 2.7 LLCPK carvedilol 6.4 MDCK diltiazem 89.2

Caco Telmisartan 10.1 LLCPK carvedilol 9.5 MDCK diltiazem 53.9

Caco Telmisartan 2.3 LLCPK carvedilol 10.9 MDCK diltiazem 53.9

Caco Telmisartan 18.1 LLCPK diltiazem 50.0 MDCK diltiazem 123.2

Caco Telmisartan 7.1 LLCPK Felodipine 30.9 MDCK diltiazem 177.3

Caco troglitazone 5.6 LLCPK isradipine 36.0 MDCK diltiazem 31.2

Caco troglitazone 13.8 LLCPK mibefradil 4.5 MDCK Felodipine 43.9

Caco troglitazone 25.6 LLCPK nicardipine 3.4 MDCK Felodipine 16.7

Caco troglitazone 7.0 LLCPK Nifedipine 126.1 MDCK Felodipine 33.9

Caco troglitazone 8.3 LLCPK quinidine 12.1 MDCK Felodipine 29.1

Caco troglitazone 15.6 LLCPK quinidine 15.7 MDCK Felodipine 34.9

Caco troglitazone 8.5 LLCPK ranolazine 55.4 MDCK Felodipine 12.7

Caco troglitazone 17.2 LLCPK Sertraline 6.8 MDCK isradipine 33.9

Caco troglitazone 40.0 LLCPK Telmisartan 21.1 MDCK isradipine 40.1

Caco verapamil 1.4 LLCPK Telmisartan 26.7 Vesicles amiodarone 1.6

MDCK isradipine 35.4 MDCK quinidine 66.7 Vesicles amiodarone 9.3

MDCK isradipine 47.9 MDCK quinidine 10.3 Vesicles amiodarone 2.6

MDCK isradipine 6.7 MDCK quinidine 8.4 Vesicles amiodarone 3.3

MDCK mibefradil 84.4 MDCK quinidine 38.4 Vesicles carvedilol 0.6

MDCK mibefradil 5.7 MDCK quinidine 30.3 Vesicles carvedilol 2.4

MDCK mibefradil 7.3 MDCK quinidine 50.7 Vesicles carvedilol 3.2

MDCK mibefradil 17.9 MDCK ranolazine 165.0 Vesicles carvedilol 2.4

MDCK mibefradil 9.6 MDCK ranolazine 36.5 Vesicles carvedilol 3.4

MDCK mibefradil 24.6 MDCK ranolazine 45.5 Vesicles diltiazem 12.5 MDCK nicardipine 0.3 MDCK ranolazine 68.2 Vesicles diltiazem 13.2

MDCK nicardipine 6.7 MDCK ranolazine 102.4 Vesicles diltiazem 12.0

MDCK nicardipine 5.1 MDCK ranolazine 114.0 Vesicles diltiazem 53.8

MDCK nicardipine 2.6 MDCK ranolazine 65.5 Vesicles diltiazem 19.2

MDCK nicardipine 7.6 MDCK Sertraline 19.6 Vesicles diltiazem 32.1

MDCK nicardipine 5.5 MDCK Sertraline 31.2 Vesicles felodipine 5.4

MDCK nicardipine 3.2 MDCK Telmisartan 35.4 Vesicles felodipine 8.6

MDCK Nifedipine 129.0 MDCK Telmisartan 12.6 Vesicles felodipine 24.1

MDCK Nifedipine 207.2 MDCK Telmisartan 3.4 Vesicles felodipine 16.1

MDCK Nifedipine 183.2 MDCK troglitazone 23.2 Vesicles felodipine 15.3

MDCK Nifedipine 77.2 MDCK troglitazone 9.3 Vesicles isradipine 8.8

MDCK Nifedipine 86.1 MDCK verapamil 26.5 Vesicles isradipine 4.6

MDCK Nifedipine 85.7 MDCK verapamil 7.1 Vesicles isradipine 16.4

MDCK Nitrendipine 30.1 MDCK verapamil 11.8 Vesicles isradipine 13.1

MDCK Nitrendipine 51.4 MDCK verapamil 25.6 Vesicles mibefradil 9.5

MDCK Nitrendipine 75.8 MDCK verapamil 32.2 Vesicles mibefradil 5.5

MDCK Nitrendipine 28.7 MDCK verapamil 20.1 Vesicles mibefradil 5.7

MDCK Nitrendipine 9.6 Vesicles amiodarone 1.5 Vesicles sertraline 14.2

Vesicles mibefradil 9.4 Vesicles nitrendipine 26.3 Vesicles sertraline 32.3

Vesicles mibefradil 6.3 Vesicles nitrendipine 14.4 Vesicles telmisartan 0.1

Vesicles mibefradil 3.2 Vesicles nitrendipine 28.1 Vesicles telmisartan 1.0

Vesicles nicardipine 0.7 Vesicles quinidine 1.0 Vesicles telmisartan 1.5

Vesicles nicardipine 1.9 Vesicles quinidine 3.2 Vesicles telmisartan 3.6

Vesicles nicardipine 1.7 Vesicles quinidine 4.5 Vesicles telmisartan 1.3

Vesicles nicardipine 1.5 Vesicles quinidine 9.8 Vesicles telmisartan 2.1

Vesicles nicardipine 3.7 Vesicles quinidine 3.3 Vesicles troglitazone 5.4

Vesicles nicardipine 2.7 Vesicles quinidine 3.9 Vesicles troglitazone 12.4

Vesicles nicardipine 2.4 Vesicles ranolazine 19.8 Vesicles troglitazone 12.3

Vesicles nifedipine 27.7 Vesicles ranolazine 2.9 Vesicles troglitazone 12.1

Vesicles nifedipine 22.9 Vesicles ranolazine 85.5 Vesicles troglitazone 10.0

Vesicles nifedipine 10.7 Vesicles ranolazine 48.7 Vesicles verapamil 1.2

Vesicles nifedipine 54.7 Vesicles ranolazine 37.6 Vesicles verapamil 3.3 Vesicles nifedipine 18.9 Vesicles sertraline 7.1 Vesicles sertraline 50.9

Vesicles nifedipine 37.1 Vesicles sertraline 7.9 Vesicles verapamil 2.5

Vesicles nitrendipine 11.1 Vesicles sertraline 6.0 Vesicles verapamil 1.9

Vesicles nitrendipine 6.5