Calibration of in Vitro MDR1 Substrate and Inhibition Assays As a Basis to Support the Prediction of Clinically Relevant Interactions in Vivo

DMD #57943

Calibration of in vitro MDR1 substrate and inhibition assays as a basis to support the prediction of clinically relevant interactions in vivo

Agnès Poirier, Anne-Christine Cascais, Urs Bader, Renée Portmann, Marie- Elise Brun, Isabelle Walter, Alexander Hillebrecht, Mohammed Ullah and Christoph Funk

Drug Metabolism and Disposition

DMD #57943

Supplemental Table 1: MDR1 substrate in vitro results of 76 CNS-related indication drugs tested in L-MDR1 cells at 1 µM ordered from lowest to highest ER

Mean Mean Mean Mean Average Papp Papp Papp Pgp Compound name Therapeutic indication Papp AB S.D. S.D. ER S.D. S.D. S.D. Pappi S.D. ERi S.D. BA ABi BAi susbtrate (nm/s) (nm/s) (nm/s) (nm/s) (nm/s)

chlorprothixene* antipsychotic 101 18 47 1 0.5 0.1 107 7 41 6 74 37 0.4 0.1 No

clozapine antipsychotic 246 30 143 17 0.6 0.1 248 43 151 1 199 60 0.6 0.1 No

duloxetine* antidepressant 140 6 84 7 0.6 0.1 185 36 101 14 143 52 0.5 0.1 No

quetiapine antipsychotic 253 7 155 4 0.6 0.1 268 22 170 4 219 55 0.6 0.1 No

nortriptylin* antidepressant 183 13 139 6 0.8 0.1 204 32 117 9 161 51 0.6 0.1 No

midazolam anesthetic 143 14 113 21 0.8 0.2 107 10 163 2 135 31 1.5 0.1 No

imipramine antidepressant 230 18 199 93 0.9 0.4 202 91 291 42 246 80 1.4 0.7 No

perphenazine* antipsychotic 108 12 105 12 1.0 0.2 95 14 104 12 99 13 1.1 0.2 No

rimonabant* anorectic 59 - 59 2 1.0 - 49 8 65 1 57 9 1.3 0.2 No

flumazenil benzodiazepine antagonist 333 16 340 10 1.0 0.1 353 10 339 17 346 15 1.0 0.1 No

selegiline* antiparkinsonian 241 6 246 21 1.0 0.1 231 7 245 12 238 12 1.1 0.1 No

diazepam anxiolytic 273 22 285 22 1.0 0.1 211 21 280 42 245 49 1.3 0.2 No

zimeldine antidepressant 276 40 303 7 1.1 0.2 236 25 345 9 291 62 1.5 0.2 No

noscapine* antitussive 189 34 209 49 1.1 0.3 187 12 276 12 231 50 1.5 0.1 No

paroxetine antidepressant 155 5 168 94 1.1 0.6 189 25 86 87 138 80 0.5 0.5 No

olanzapine** antipsychotic 720 25 784 16 1.1 0.1 371 46 518 28 445 87 1.4 0.2 No

buspirone anxiolytic 290 14 326 27 1.1 0.1 305 31 325 31 315 30 1.1 0.1 No

DMD #57943

Mean Mean Mean Mean Average Papp Papp Papp Pgp Compound name Therapeutic indication Papp AB S.D. S.D. ER S.D. S.D. S.D. Pappi S.D. ERi S.D. BA ABi BAi susbtrate (nm/s) (nm/s) (nm/s) (nm/s) (nm/s)

scopolamine antiemetic 261 13 293 38 1.1 0.2 224 28 307 15 265 50 1.4 0.2 No

oxycodone analgesic 275 17 316 17 1.2 0.1 276 42 289 13 283 29 1.0 0.2 No

codeine analgesic 258 22 297 10 1.2 0.1 244 11 318 24 281 44 1.3 0.1 No

progabide* anticonvulsant 194 3 224 15 1.2 0.1 172 10 200 24 186 24 1.2 0.2 No

procyclidine antiparkinsonian 232 13 271 15 1.2 0.1 215 11 302 13 258 49 1.4 0.1 No

trimipramine antidepressant 217 39 254 21 1.2 0.2 232 14 245 14 238 14 1.1 0.1 No

meprobamate anxiolytic 190 32 225 12 1.2 0.2 190 6 225 4 208 20 1.2 0.1 No

amantadine antiviral, antiparkinsonian 294 33 351 7 1.2 0.1 277 13 336 18 307 35 1.2 0.1 No

haloperidol antipsychotic 241 14 288 19 1.2 0.1 231 5 287 30 259 37 1.2 0.1 No

amitryptilline* antidepressant 178 40 209 93 1.2 0.6 162 50 270 9 216 67 1.7 0.5 No

doxepin antidepressant 222 44 260 44 1.2 0.3 185 34 295 30 240 67 1.6 0.3 No

ketamine anesthetic 307 10 368 13 1.2 0.1 273 25 370 19 321 57 1.4 0.1 No

memantine Alzheimer's disease 322 30 377 23 1.2 0.1 305 14 335 12 320 20 1.1 0.1 No

venlafaxine antidepressant 287 43 352 39 1.2 0.2 321 63 438 31 379 78 1.4 0.3 No

zolpidem sedative 304 37 365 36 1.2 0.2 251 12 307 20 279 34 1.2 0.1 No

carbamazepine anticonvulsant 357 18 429 35 1.2 0.1 345 49 428 36 387 60 1.2 0.2 No

maprotiline* antidepressant 158 16 191 3 1.2 0.1 142 2 178 2 160 21 1.3 0.1 No

alfentanil opioid analgesic 257 12 312 4 1.2 0.1 205 21 281 5 243 44 1.4 0.1 No

tramadol analgesic 264 16 339 11 1.3 0.1 259 28 332 40 295 51 1.3 0.2 No

DMD #57943

Mean Mean Mean Mean Average Papp Papp Papp Pgp Compound name Therapeutic indication Papp AB S.D. S.D. ER S.D. S.D. S.D. Pappi S.D. ERi S.D. BA ABi BAi susbtrate (nm/s) (nm/s) (nm/s) (nm/s) (nm/s)

phenytoin antiepileptic 227 32 294 22 1.3 0.2 224 34 296 22 260 47 1.3 0.2 No

alprazolam anxiolytic 265 23 344 61 1.3 0.3 289 10 354 22 322 39 1.2 0.1 No

bupropion antidepressant 233 18 294 4 1.3 0.1 247 33 337 17 292 54 1.4 0.2 No

escitalopram antidepressant 296 43 399 31 1.3 0.2 279 21 366 25 323 52 1.3 0.1 No

metergoline analgesic, antipyretic 129 16 170 4 1.3 0.2 90 51 160 4 125 46 1.8 1.0 No

moclobemide antidepressant 290 29 378 70 1.3 0.3 341 35 389 39 365 42 1.1 0.2 No

nitrazepam anticonvulsant 245 40 322 5 1.3 0.2 235 28 317 33 276 52 1.3 0.2 No

promazine antipsychotic 160 36 218 18 1.4 0.3 133 25 234 17 184 58 1.8 0.3 No

naltrexone narcotic antagonist 287 19 395 37 1.4 0.2 305 25 364 29 335 40 1.2 0.1 No

tacrine cognitive stimulant 294 31 411 71 1.4 0.3 274 10 383 14 329 61 1.4 0.1 No

aripiprazole antipsychotic 89 6 123 18 1.4 0.2 73 8 101 11 87 18 1.4 0.2 No

clomipramine antidepressant 124 12 168 20 1.4 0.2 135 10 202 82 169 69 1.5 0.6 No

pentobarbital sedative 243 44 339 30 1.4 0.3 202 45 293 26 247 60 1.4 0.3 No

triazolam benzodiazepine 215 36 292 20 1.4 0.2 227 15 292 18 260 39 1.3 0.1 No

trazodone antidepressant 62 13 88 5 1.4 0.3 53 1 91 9 72 22 1.7 0.2 No

nordazepam anxiolytic 220 49 316 29 1.4 0.3 201 26 302 19 251 59 1.5 0.2 No

oxymorphone analgesic 142 7 210 17 1.5 0.1 158 9 189 18 173 21 1.2 0.1 No

flurazepam anxiolytic 211 21 316 46 1.5 0.3 203 8 317 22 260 64 1.6 0.1 No

sertraline antidepressant 95 14 145 16 1.5 0.3 89 13 149 13 119 35 1.7 0.3 No

DMD #57943

Mean Mean Mean Mean Average Papp Papp Papp Pgp Compound name Therapeutic indication Papp AB S.D. S.D. ER S.D. S.D. S.D. Pappi S.D. ERi S.D. BA ABi BAi susbtrate (nm/s) (nm/s) (nm/s) (nm/s) (nm/s)

naloxone narcotic antagonist 122 5 191 52 1.6 0.4 301 4 276 35 289 24 0.9 0.1 No

levomeprazine antipsychotic 122 20 192 15 1.6 0.3 125 24 204 6 164 46 1.6 0.3 No

chlorpromazine antipsychotic 87 15 139 13 1.6 0.3 84 9 121 5 102 21 1.4 0.2 No

donepezil Alzheimer's disease 234 31 364 24 1.6 0.2 193 33 314 39 254 74 1.6 0.3 No

biperiden antiparkinsonian 185 3 298 19 1.6 0.1 218 15 291 16 254 42 1.3 0.1 No

fluoxetine antidepressant 121 8 198 11 1.6 0.1 159 17 175 80 167 52 1.1 0.5 No

fluvoxamine antidepressant 220 20 374 30 1.7 0.2 236 23 248 59 242 40 1.0 0.3 No

nalbuphine analgesic 248 62 452 158 1.8 0.8 268 105 300 37 284 72 1.1 0.5 No

morphine analgesic 57 8 105 4 1.8 0.3 63 5 73 6 68 8 1.2 0.1 No

desipramine antidepressant 147 42 276 98 1.9 0.9 322 121 462 62 392 115 1.4 0.6 No

citalopram antidepressant 227 29 448 15 2.0 0.3 247 36 235 101 241 68 1.0 0.4 Yes

diphenhydramine anxiolytic / antihistamine 175 51 348 46 2.0 0.6 246 100 326 47 286 82 1.3 0.6 Yes

protriptylin antidepressant 136 12 301 8 2.2 0.2 182 21 240 24 211 37 1.3 0.2 Yes

atropine* anticholinergic 94 0 323 8 3.4 0.1 129 14 161 13 145 21 1.2 0.2 Yes

paliperidone antipsychotic 130 24 457 33 3.5 0.7 249 44 329 130 289 97 1.3 0.6 Yes

zolmitriptan antimigraine 5 1 19 2 3.6 0.9 6 1 11 1 9 3 1.9 0.3 Yes

lorazepam anxiolytic 77 1 287 29 3.7 0.4 224 39 110 10 167 68 0.5 0.1 Yes

methysergide antimigraine 118 16 445 104 3.8 1.0 261 29 287 36 274 33 1.1 0.2 Yes

risperidone antipsychotic 140 37 559 246 4.0 2.1 224 23 249 43 236 34 1.1 0.2 Yes

DMD #57943

Mean Mean Mean Mean Average Papp Papp Papp Pgp Compound name Therapeutic indication Papp AB S.D. S.D. ER S.D. S.D. S.D. Pappi S.D. ERi S.D. BA ABi BAi susbtrate (nm/s) (nm/s) (nm/s) (nm/s) (nm/s)

bromocriptine antiparkinsonian 27 4 196 5 7.2 1.1 66 13 105 2 85 23 1.6 0.3 Yes

eletriptan antimigraine 25 0 698 145 27.6 5.7 287 25 370 31 329 52 1.3 0.2 Yes

digoxin‡ antiarrhythmic 5 0 148 4 28.3 1.1 43 1 58 2 51 8 1.3 0.1 Yes

* recovery between 60 and 70%

** recovery above 130%

‡ positive control digoxin (tested at 5 µM)

Unless otherwise stated, all compounds were tested at 1 µM and recoveries (mass balance) were within the acceptance range of 70-120%. Three compounds that were tested failed due to apparent low permeability (all samples were below the limit of detection, mostly average Pappi < 15 nm/s): baclofen, gabapentin, sumatriptan.

DMD #57943

Supplemental Table 2: MDR1 substrate in vitro results of 91 non CNS-related indication drugs tested in L-MDR1 cells at 1 µM ordered from lowest to highest ER

Mean Mean Mean Mean Average P P P Pgp Compound name Therapeutic indication P AB S.D. app S.D. ER S.D. app S.D. app S.D. P i S.D. ERi S.D. app BA ABi BAi app substrate (nm/s) (nm/s) (nm/s) (nm/s) (nm/s) enalaprilat ACE inhibitor 8 0 4 0 0.5 0.1 9 0 5 1 7 2 0.6 0.2 No antipyrine local analgesic 335 21 330 8 1.0 0.1 317 27 336 3 326 20 1.1 0.1 No mexiletine antiarrythmic 343 20 340 9 1.0 0.1 344 16 357 26 351 20 1.0 0.1 No isotretinoin chemotherapy 34 2 34 3 1.0 0.1 23 15 40 2 32 13 1.7 1.1 No lidocaine local anesthetic 324 14 344 27 1.1 0.1 318 19 303 16 310 18 1.0 0.1 No promethazine* antihistamine 205 1 225 6 1.1 0.0 181 31 266 16 224 51 1.5 0.3 No felodipine antihypertensive 99 12 108 16 1.1 0.2 68 6 121 14 94 31 1.8 0.3 No chlorpheneramine antihistamine 342 15 366 9 1.1 0.1 338 20 358 22 348 22 1.1 0.1 No cyclobenzaprine muscle relaxer 187 9 220 15 1.2 0.1 161 14 205 11 183 26 1.3 0.1 No fenofibrate hypercholesterolemia 49 21 58 10 1.2 0.5 34 11 79 27 56 31 2.3 1.1 No dextromethorphan antitussive (hallucinogen) 316 19 384 79 1.2 0.3 291 119 382 26 336 92 1.3 0.5 No doxylamine antihistamine 332 25 384 31 1.2 0.1 327 22 317 - 322 18 1 - No clemastine* antihistamine 145 25 182 2 1.3 0.2 129 13 157 9 143 19 1.2 0.1 No fumitremorgin C mycotoxin 285 12 364 8 1.3 0.1 273 50 294 12 284 34 1.1 0.2 No clonidine antihypertensive 288 8 374 17 1.3 0.1 260 31 344 20 302 51 1.3 0.2 No nitrendipine antihypertensive 157 2 207 10 1.3 0.1 200 23 213 19 207 20 1.1 0.2 No pheniramine antihistamine 293 22 368 16 1.3 0.1 300 28 348 25 324 36 1.2 0.1 No bufuralol antihypertensive 174 5 234 16 1.3 0.1 175 9 251 24 213 45 1.4 0.2 No alprenolol antihypertensive 215 39 293 15 1.4 0.3 232 13 305 14 268 42 1.3 0.1 No gemfibrozil hypercholesterolemia 70 12 95 5 1.4 0.2 66 8 98 5 82 19 1.5 0.2 No pioglitazone antidiabetic 128 16 183 56 1.4 0.5 117 2 174 31 145 36 1.5 0.3 No metoprolol antihypertensive 236 12 339 61 1.4 0.3 236 81 322 56 279 78 1.4 0.5 No cisapride gastroprokinetic agent 191 11 292 2 1.5 0.1 200 31 247 6 224 33 1.2 0.2 No nimodipine antihypertensive 159 22 246 35 1.5 0.3 108 19 192 13 150 49 1.8 0.3 No lorcainide antiarrythmic 211 8 307 20 1.5 0.1 204 49 282 23 243 55 1.4 0.3 No pindolol beta blocker 219 21 337 10 1.5 0.2 218 28 251 29 234 32 1.2 0.2 No oxprenolol antihypertensive 194 32 300 18 1.5 0.3 184 14 287 17 235 58 1.6 0.2 No warfarin anticoagulant 77 3 121 9 1.6 0.1 82 9 109 5 95 16 1.3 0.2 No ezetimibe hypercholesterolemia 101 17 159 - 1.6 - 105 9 185 13 145 45 1.8 0.2 No 7

DMD #57943

Mean Mean Mean Mean Average P P P Pgp Compound name Therapeutic indication P AB S.D. app S.D. ER S.D. app S.D. app S.D. P i S.D. ERi S.D. app BA ABi BAi app substrate (nm/s) (nm/s) (nm/s) (nm/s) (nm/s) simvastatin hypercholesterolemia 38 12 61 20 1.6 0.7 54 4 51 12 52 8 0.9 0.2 No piroxicam NSAID 191 14 316 5 1.7 0.1 235 51 290 16 263 45 1.2 0.3 No propranolol antihypertensive 213 56 361 78 1.7 0.6 215 27 353 14 284 78 1.6 0.2 No doxapram respiratory stimulant 231 28 396 23 1.7 0.2 238 6 312 12 275 41 1.3 0.1 No indomethacin anti-inflammatory 90 16 167 8 1.9 0.3 81 7 167 21 124 49 2.1 0.3 No ketoprofen NSAID 77 11 145 16 1.9 0.3 71 25 120 50 96 45 1.7 0.9 No diltiazem anti-anginal 184 49 372 57 2.0 0.6 267 22 345 32 306 49 1.3 0.2 Yes hydrochlorothiazide diuretic 15 6 31 3 2.1 0.8 10 4 22 4 16 8 2.2 1.0 Yes genistein isoflavone 64 12 135 16 2.1 0.5 121 10 169 20 145 30 1.4 0.2 Yes ranitidine antihistamine 7 0 16 4 2.2 0.5 8 0 7 6 8 4 0.8 0.7 Yes zidovudine antiretroviral 33 7 73 1 2.2 0.5 32 4 79 6 56 26 2.4 0.4 Yes lovastatin hypercholesterolemia 109 22 240 22 2.2 0.5 121 16 223 6 172 57 1.8 0.3 Yes levofloxacine chemotherapy 45 3 100 8 2.2 0.2 43 1 80 8 62 21 1.9 0.2 Yes 82 111 28 mequitazine* antihistamine 87 5 207 31 2.4 1.4 96 27 1.4 Yes trimethoprim antibacterial 81 1 231 91 2.9 1.1 196 25 218 10 207 21 1.1 0.2 Yes verapamil antianginal 131 22 385 30 3.0 0.5 170 41 224 86 197 67 1.3 0.6 Yes guanfacine antihypertensive 129 8 393 30 3.0 0.3 199 23 242 4 220 29 1.2 0.1 Yes cetirizine antihistamine 36 5 124 6 3.5 0.5 50 2 64 17 57 14 1.3 0.4 Yes astemizole* antihistamine 29 5 102 4 3.6 0.6 28 4 40 5 34 8 1.4 0.3 Yes daidzein isoflavone 88 8 330 58 3.7 0.7 87 13 239 67 163 96 2.7 0.9 Yes sunitinib* chemotherapy 76 4 314 4 4.1 0.3 74 10 119 3 96 26 1.6 0.2 Yes prazosin antihypertensive 116 13 494 95 4.2 0.9 226 13 349 22 287 69 1.5 0.1 Yes topotecan*† chemotherapy <9 - 39 9 >4.2 1.0 13 4 21 4 17 6 1.6 0.6 Yes acrivastine antihistamine 18 1 80 2 4.5 0.3 32 1 36 3 34 3 1.1 0.1 Yes doxorubicin chemotherapy <19 - 83 8 >4.5 0.4 19 0 8 1 14 6 0.4 0.0 Yes pitavastatin hypercholesterolemia 12 3 60 3 5.0 1.1 19 7 45 1 32 15 2.3 0.9 Yes cilazapril ACE inhibitor 3 0 16 0 5.3 0.8 6 1 7 2 7 1 1.1 0.3 Yes sildenafil erectile dysfunction 86 19 463 71 5.4 1.5 228 29 331 36 279 63 1.5 0.2 Yes famciclovir* antiviral 28 20 159 24 5.8 4.4 34 27 143 38 88 67 4.3 3.5 inconclusive mitoxantrone chemotherapy <26 - 150 9 >5.8 0.3 28 0 48 7 38 12 1.7 0.3 Yes atorvastatin hypercholesterolemia 5 1 26 5 5.9 1.5 15 5 6 1 11 6 0.4 0.1 Yes paclitaxel chemotherapy 34 12 224 12 6.5 2.2 47 9 104 4 75 32 2.2 0.4 Yes 8

DMD #57943

Mean Mean Mean Mean Average P P P Pgp Compound name Therapeutic indication P AB S.D. app S.D. ER S.D. app S.D. app S.D. P i S.D. ERi S.D. app BA ABi BAi app substrate (nm/s) (nm/s) (nm/s) (nm/s) (nm/s) MK571 bronchodilator 16 1 106 9 6.7 0.8 40 2 64 3 52 13 1.6 0.1 Yes SN38 chemotherapy 11 4 77 9 7.1 2.8 28 1 46 2 37 11 1.7 0.1 Yes fluvastatin hypercholesterolemia <9 - 63 5 >7.3 0.6 13 2 38 5 26 14 3.0 0.7 Yes terfenadine antihistamine 6 0 49 15 7.8 2.4 10 19 3 14 5 2.1 Yes gefitinib chemotherapy 42 3 344 33 8.1 1.0 55 7 112 7 84 32 2.0 0.3 Yes labetolol antihypertensive 44 16 390 167 8.8 4.9 178 9 198 67 188 44 1.1 0.4 Yes colchicine alkaloid 4 0 39 2 9.2 0.8 7 2 11 0 9 2 1.5 0.4 Yes carvedilol beta blocker 15 5 162 10 10.6 3.8 66 20 105 46 85 38 1.6 0.9 Yes amlodipine antihypertensive 35 3 415 33 11.8 1.4 90 4 113 9 101 14 1.3 0.1 Yes glybenclamide antidiabetic 6 1 73 12 11.8 3.1 36 2 51 4 43 9 1.4 0.1 Yes cimetidine anti-ulcerative 20 11 260 63 12.7 7.4 17 5 53 11 35 21 3.0 1.0 Yes loperamide antidiarrheal 35 8 448 34 12.9 3.1 122 41 212 5 167 56 1.7 0.6 Yes imatinib chemotherapy 28 3 396 41 14.2 2.2 124 29 200 26 162 48 1.6 0.4 Yes saquinavir antiviral <4 - 60 2 >16.4 0.6 26 1 36 8 31 8 1.4 0.3 Yes erythromycine antibiotic <3 - 54 4 >17.0 1.3 15 5 25 6 20 8 1.7 0.7 Yes sitagliptin antidiabetic 11 1 197 16 17.7 2.3 66 6 78 6 72 9 1.2 0.1 Yes domperidone antiemetic 30 2 560 107 18.7 3.7 105 12 268 44 187 94 2.6 0.5 Yes talinolol beta-blocker 5 0 103 11 19.0 2.1 24 4 34 3 29 6 1.4 0.3 Yes irinotecan chemotherapy 2 0 49 17 29.1 12.3 16 4 26 2 21 6 1.6 0.4 Yes rifampicin antibiotic 6 2 175 1 29.6 8.3 33 2 49 4 41 9 1.5 0.1 Yes neostigmine cholinergic agent 5 1 159 3 29.7 4.0 5 0 7 0 6 1 1.4 0.2 Yes daunorubicine chemotherapy <19 - 667 30 >35.0 1.6 85 12 109 5 97 15 1.3 0.2 Yes vinblastine chemotherapy 8 1 284 12 36.7 6.8 64 5 114 11 89 28 1.8 0.2 Yes cyclosporine A immunosuppressant 6 1 219 35 37.1 10.5 60 8 76 12 68 13 1.3 0.3 Yes amprenavir antiviral 10 0 418 115 42.8 11.8 163 1 220 6 192 31 1.3 0.1 Yes 48 1 68 nelfinavir antiviral <4 - 169 23 >46.0 6.3 58 12 1.4 Yes indinavir antiviral <4 - 232 26 >53.7 6.0 85 3 131 8 108 26 1.5 0.1 Yes ritonavir antiviral 2 1 129 3 56.5 12.4 65 8 88 5 76 14 1.3 0.2 Yes furosemide diuretic <19 - 21 3 >1.1 0.2 37 5 36 3 36 4 1.0 0.2 inconclusive E3S not applicable 31 7 26 8 0.8 0.3 32 9 15 4 24 11 0.5 0.2 No digoxin‡ antiarrhythmic 5 0 148 4 28.3 1.1 43 1 58 2 51 8 1.3 0.1 Yes

DMD #57943

*recovery between 60 and 70% ** recovery above 130%

† tested at 0.5 µM (toxic at 1 µM)

‡ positive control digoxin (tested at 5 µM)

Unless otherwise stated, all compounds were tested at 1 µM and recoveries (mass balance) were within the acceptance range of 70-120%. When PappAB could not be estimated as associated samples were below the limit of quantification, a value was calculated using the limit of detection and is indicated as “<” to this value, equally the ER is estimated to be “>” the calculated ratio

Twenty-six more compounds were tested but failed in this high throughput screening setup due to:

o not compatible with the high throughput analytic method: mannitol, docetaxel, tacrolimus, lamivudine

o compound being instable or not soluble (1mM in DMSO): guanabenz, nisoldipine, pirenzepine, captopril, nifedipine

o an apparent low permeability (all samples below the limit of detection, mostly average Pappi < 15 nm/s): losartan, fexofenadine, amoxicillin, cephalexin, sulfasalazine, atenolol, naproxen, lisinopril, terbutaline,

vincristine, coumestrol, methotrexate, rosuvastatin, metformin, tamoxifen, nitrofurantoin, valsartan

DMD #57943

Supplemental Table 3: Digoxin clinical DDI studies (training set) ordered by greatest plasma exposure ratio : victim and perpetrator name, perpetrator plasma and gut concentrations, perpetrator fup, victim AUC, Cmax and CLrenal fold ratios.

[I2] was calculated as dose/250 ml converted into µM, in case of multiple dosing per day, only single doses are considered. fup was approximated to 0.01 if the published value was below; in case of conflicting values or concentration- dependent protein binding, the most conservative value was kept i.e. the highest fup value giving to the highest [I1u]. † in combination with ritonavir 100 mg. * calculated as [I1T] x fup. ** information from the Metabolism and Transport Drug

Interaction Database from University of Washington (for [I1T] if needed, levels were adjusted to the dose assuming dose linearity). # 70 kg body weight was assumed to calculate the dose (referenced as 20 mg/kg in (Sechaud et al., 2008)). AUCi/AUC > 1.25 or Cmax,i,ss/Cmax,ss > 1.25 characterized a relevant clinical DDI

(below dashed line); AUCi/AUC < 1.25 and Cmax,i,ss/Cmax,ss < 1.25 characterized a non-significant clinical DDI (above dashed line) (Ellens et al., 2013).

Perpetrator Perpetrator Perpetrator Perpetrator Cmax,i,ss/Cmax,ss CLi/CLrenal Victim drug Perpetrator Ref Ref Ref AUCi/AUC ratio Ref Ref Ref [I1T] fup [I1u] [I2] ratio ratio

(µM) (µM) * (µM)

digoxin Aliskiren 0.435 6 0.51 ** 0.220 2175 6 0.86 6 0.92 6 -

digoxin Deferasirox# 75.5 12 0.01 ** 0.755 14997 12 0.91 12 0.93 12 0.95 12

digoxin Ramelteon 0.0093 ** 0.18 2 0.00168 247 2 0.95 2 0.92 2 -

digoxin Erythromycin 4.70 4 0.15 15 0.705 1090 47 0.96 4 1.00 4 1.39 47

digoxin Levofloxacin 23.0 50 0.69 ** 15.87 5534 50 0.99 50 0.92 50 1.04 50

digoxin Orlistat 0.0070 4 0.01 ** 0.00007 968 49 0.99 4 0.95 4 -

digoxin Varenicline 0.0300 1 0.80 22 0.0240 11 22 1.00 1 1.00 1 1.11 22

digoxin Citalopram 0.230 4 0.20 ** 0.0460 493 48 1.01 4 0.96 4 0.94 48

digoxin Sparfloxacin 2.50 4 0.60 ** 1.50 2039 51 1.02 4 0.92 4 -

digoxin Atorvastatin 0.0200 1 0.02 2 0.00040 72 26 1.03 1 1.10 1 -

digoxin Captopril 1.38 ** 0.75 2 1.04 230 23 1.03 2 0.95 2 -

DMD #57943

Perpetrator Perpetrator Perpetrator Perpetrator Cmax,i,ss/Cmax,ss CLi/CLrenal Victim drug Perpetrator Ref Ref Ref AUCi/AUC ratio Ref Ref Ref [I1T] fup [I1u] [I2] ratio ratio

(µM) (µM) * (µM)

digoxin Meloxicam 5.41 4 0.01 ** 0.0541 171 52 1.03 4 1.03 4 -

digoxin Repaglinide 0.100 4 0.03 ** 0.00260 18 53 1.03 4 1.03 4 -

digoxin Rofecoxib 1.02 ** 0.13 2 0.133 954 43 1.04 2 1.00 2 -

digoxin Rosuvastatin 0.0170 3 0.12 ** 0.00204 160 3 1.04 3 1.04 3 -

digoxin Troglitazone 3.62 1 0.01 ** 0.0362 3624 30 1.04 1 1.05 1 -

digoxin Losartan 0.490 3 0.01 ** 0.00637 473 3 1.06 3 1.13 3 -

digoxin Nicardipine 0.180 1 0.05 2 0.00900 250 28 1.06 1 1.06 1 -

digoxin Mibefradil 0.807 1 0.01 2 0.00807 404 38 1.08 39 1.22 39 -

digoxin Dipyridamole 3.70 4 0.01 2 0.0370 1189 7 1.08 7 1.23 7 1.08 7

digoxin Montelukast 0.890 4 0.01 ** 0.00890 68 54 1.09 4 1.00 4 -

digoxin Nitrendipine 0.0150 1 0.01 2 0.00015 111 32 1.09 32 1.22 32 1.11 32

digoxin Midazolam 0.0320 2 0.02 2 0.00064 25 25 1.10 2 1.05 2 -

digoxin Omeprazole 2.20 3 0.05 ** 0.110 232 3 1.10 3 1.10 3 -

digoxin Sertraline 0.390 1 0.01 2 0.00390 2612 29 1.10 1 1.05 1 -

digoxin Pantoprazole 5.78 4 0.02 ** 0.116 370 55 1.11 4 1.10 4 -

digoxin Sitagliptin 0.950 3 0.62 ** 0.589 765 3 1.11 3 1.18 3 -

digoxin Atorvastatin 0.330 1 0.02 2 0.00660 573 26 1.15 1 1.20 1 -

digoxin Eplerenone 4.51 2 0.40 2 1.80 965 44 1.16 2 1.05 2 -

digoxin Nifedipine 0.460 1 0.04 2 0.0184 231 31 1.18 1 1.08 1 0.92 1

DMD #57943

Perpetrator Perpetrator Perpetrator Perpetrator Cmax,i,ss/Cmax,ss CLi/CLrenal Victim drug Perpetrator Ref Ref Ref AUCi/AUC ratio Ref Ref Ref [I1T] fup [I1u] [I2] ratio ratio

(µM) (µM) * (µM)

digoxin Etravirine 1.89 11 0.01 ** 0.0189 1838 11 1.19 11 1.18 11 -

digoxin Nifedipine 0.110 1 0.04 2 0.00440 58 31 1.21 1 1.01 1 -

digoxin Nifedipine 0.230 1 0.04 2 0.00920 116 31 1.23 1 1.06 1 0.99 1

digoxin Carvedilol 0.130 1 0.05 ** 0.00650 62 34 1.24 1 1.00 1 -

digoxin Diltiazem 0.700 1 0.22 2 0.154 868 37 1.24 1 1.24 1 0.84 1

relevant DDI due to AUCi/AUC ratio >1.25

digoxin Mibefradil 2.42 1 0.01 2 0.0242 1211 38 1.31 1 1.41 1 -

digoxin Captopril 0.230 1 0.75 2 0.173 230 39 1.39 1 1.59 1 -

digoxin Dronedarone 0.192 ** 0.01 ** 0.00192 2874 8 1.41 8 - -

digoxin Conivaptan 1.16 1 0.01 ** 0.0116 321 40 1.43 1 1.79 1 -

digoxin Diltiazem 0.700 1 0.22 2 0.154 579 41 1.44 1 1.38 1 -

digoxin Diltiazem 0.170 3 0.22 2 0.0374 579 3 1.51 3 1.37 3 -

digoxin Verapamil 1.20 1 0.09 2 0.112 704 27 1.51 1 1.44 1 1.04 1

digoxin Carvedilol 0.130 1 0.05 2 0.00650 62 34 1.56 1 1.38 1 -

digoxin Ranolazine 8.60 3 0.38 ** 3.27 9356 3 1.60 3 1.46 3 0.54 1

digoxin Amiodarone 2.49 1 0.01 2 0.0249 2479 1 1.63 1 1.72 1 1.00 1

digoxin Clarithromycin 2.70 3 0.50 2 1.35 1337 3 1.64 3 1.83 3 -

digoxin Amiodarone 2.20 1 0.01 2 0.0220 4959 1 1.68 1 1.84 1 1.00 1

digoxin Itraconazole 0.950 3 0.01 2 0.00950 1134 3 1.68 3 1.34 3 -

DMD #57943

Perpetrator Perpetrator Perpetrator Perpetrator Cmax,i,ss/Cmax,ss CLi/CLrenal Victim drug Perpetrator Ref Ref Ref AUCi/AUC ratio Ref Ref Ref [I1T] fup [I1u] [I2] ratio ratio

(µM) (µM) * (µM)

digoxin Valspodar 0.510 1 0.85 ** 0.434 1317 1 1.74 1 1.72 1 0.35 1

digoxin Quinidine 3.54 1 0.16 2 0.566 3397 1 1.76 1 1.75 1 -

digoxin Darunavir† 9.20 ** 0.05 ** 0.460 4042 9 1.77 9 - -

digoxin Quinidine 5.10 1 0.16 2 0.816 2466 56 2.65 1 - 1 0.66 56

digoxin Valspodar 1.54 1 0.85 ** 1.31 659 1 3.05 1 2.44 1 0.25 1

relevant DDI due to Cmax,i,ss/Cmax,ss > 1.25

digoxin Mibefradil 1.613 1 0.01 2 0.0161 807 38 1.07 39 1.25 39 -

digoxin Isradipine 0.0200 1 0.05 2 0.00100 54 27 1.11 1 1.26 1 1.04 1

digoxin Tolvaptan 0.960 10 0.02 ** 0.0192 535 10 1.18 10 1.27 10 0.41 10

digoxin Etoricoxib 10.0 ** 0.08 2 0.800 1338 24 1.06 2 1.33 2 -

digoxin Propafenone 0.650 1 0.10 ** 0.0650 1757 46 - 1.33 1 -

digoxin Felodipine 0.0300 1 0.01 2 0.00030 104 33 1.18 1 1.34 1 -

digoxin Cyclosporin A 2.80 3 0.05 2 0.126 1167 3 - 3 1.44 3 -

digoxin Quinidine 4.50 3 0.16 2 0.720 2466 3 - 3 1.44 3 -

digoxin Talinolol 0.620 2 0.49 2 0.304 1100 45 1.23 2 1.45 2 -

digoxin Verapamil 0.0258 57 0.09 2 0.00240 704 57 - 1.53 57 -

digoxin Nitrendipine 0.0300 1 0.01 2 0.00030 222 32 1.15 1 1.57 1 0.87 32

digoxin Telmisartan 1.11 1 0.01 ** 0.0111 933 36 1.22 1 1.58 1 -

digoxin Carvedilol 0.520 1 0.05 ** 0.0260 246 35 1.20 1 1.60 1 0.87 1

DMD #57943

Perpetrator Perpetrator Perpetrator Perpetrator Cmax,i,ss/Cmax,ss CLi/CLrenal Victim drug Perpetrator Ref Ref Ref AUCi/AUC ratio Ref Ref Ref [I1T] fup [I1u] [I2] ratio ratio

(µM) (µM) * (µM)

digoxin Verapamil 0.0577 56 0.09 2 0.00537 1056 56 - 1.61 56

digoxin Verapamil 0.0332 56 0.09 2 0.00309 704 56 - 1.77 56 -

DMD #57943

Supplemental Table 4: Clinical DDI studies (test set) ordered by greatest plasma exposure ratio: victim and perpetrator name, perpetrator gut concentration, victim greatest plasma exposure fold ratio

(AUC or Cmax), victim CLrenal fold ratios and perpetrator IC50(ER)

[I2] was calculated as dose/250 ml converted into µM, in case of multiple dosing per day, only single doses are considered. AUCi/AUC > 1.25 or Cmax,i,ss/Cmax,ss > 1.25 characterized a relevant clinical DDI

(below dashed line); AUCi/AUC < 1.25 and Cmax,i,ss/Cmax,ss < 1.25 characterized a non-significant clinical DDI (above dashed line) (Ellens et al., 2013). * IC50 using talinolol as probe substrate at 1µM Greatest [I2] / Perpetrator plasma CLi/CLrenal S.D. Victim drug Perpetrator Ref Ref Ref IC50(ER) ER [I2] exposure ratio IC50(ER) IC50 ratio

(µM) (µM) (µM)

Candesartan digoxin 145 58 0.95 58 - - 51.7 6.7 2.8 cilexetil

digoxin Dapagliflozin 98 58 1.00 58 - - > 100 - 1.0

digoxin Maraviroc 2335 58 1.01 58 - - > 600 - 3.9

digoxin Linagliptin 42 58 1.01 58 - - > 100 - 0.4

digoxin Disopyramide 793 58 1.01 58 - - > 3000 - 0.3

digoxin Donepezil 53 58 1.03 58 - - 31.2 4.9 1.7

Dabigatran digoxin 955 58 1.11 58 - - > 1000 - 1.0 etexilate

digoxin Ambrisentan 106 58 1.30 58 - - > 1000 - 0.1

digoxin Flecaine 1931 58 1.35 58 - - 39.7 10.4 49

digoxin Rifampin 2920 58 1.49 58 - - 155 36 19

digoxin Lapatinib 8605 58 2.80 58 - - 3.5 0.4 2459

fexofenadine Omeprazole 463 5 1.01 5 - - 110 46 4

fexofenadine Diltiazem 965 14 1.07 14 - - 4.6 0.2 210

fexofenadine Cimetidine 6341 13 1.08 13 0.61 13 >2000 - 3

fexofenadine Verapamil 2112 17 1.80 17 0.82 17 2.8 0.5 754

fexofenadine Erythromycin 2725 5 2.03 5 - - >300 - 9

fexofenadine Itraconazole 283 16 2.09 16 0.93 16 1.8 0.4 157

fexofenadine Erythromycin 1635 5 2.09 15 - - >300 - 5

fexofenadine Ritonavir 555 5 2.23 18 - - 21.3 1.3 26

fexofenadine Itraconazole 1134 16 2.41 16 1.01 16 1.8 0.4 630

fexofenadine Verapamil 704 13 2.92 13 0.95 13 2.8 0.5 251

fexofenadine Itraconazole 567 16 2.53 16 1.04 16 1.8 0.4 315

DMD #57943

fexofenadine Ketoconazole 3013 5 2.64 15 - - 1.2 0.3 2511

fexofenadine Itraconazole 567 14 2.73 14 - - 1.8 0.4 315

Greatest [I2] Perpetrator plasma CLi/CLrenal S.D. Victim drug Perpetrator Ref Ref Ref IC50(ER) / ER [I2] exposure ratio IC50(ER) IC50 ratio

(µM) (µM) (µM)

talinolol Verapamil 1056 20 0.76 20 1.01 20 4.6* 1.2 230

talinolol Simvastatin 382 5 1.13 21 1.03 21 >300* - 1

talinolol Erythromycin 10900 19 1.52 19 0.98 19 >300* - 36

DMD #57943

Supplemental Table 5: Accuracy, false negative rate, precision, sensitivity and specificity of the different models for the prediction of digoxin MDR1-mediated clinical DDI: free and total [I1]/IC50 and [I2]/IC50 (using different IC50s and the training set).

Predictor Threshold* Accuracy FN rate Precision Sensitivity Specificity

% % % % %

0.1 66 48 71 52 80 [I1T]/IC50(ER) 0.00164 66 6 60 94 40

0.1 65 67 85 33 94 [I1T]/IC50(PappAB) 0.000975 60 6 55 94 29

0.1 66 61 81 39 91 [I1T]/IC50(PappBA) 0.000975 60 6 55 94 29

0.1 60 82 100 18 100 [I1u]/IC50(ER) 0.000103 65 6 58 94 37

0.1 54 94 100 6 100 [I1u]/IC50(PappAB) 0.0000302 63 6 57 94 34

0.1 56 91 100 9 100 [I1u]/IC50(PappBA) 0.0000302 63 6 57 94 34

10 82 9 77 91 74 [I2]/IC50(ER) 6.55 82 6 76 94 71

10 78 24 78 76 80 [I2]/IC50(PappAB) 1.79 73 6 66 94 54

10 76 30 79 70 83 [I2]/ IC50(PappBA) 1.81 73 6 66 94 54

*the first threshold correspond to the FDA proposal; the second threshold has been refined by the ROC analysis

DMD #57943

Supplemental Data Table 3 and 4 References 1. Fenner, K.S., et al., Drug-drug interactions mediated through P-glycoprotein: clinical relevance and in vitro-in vivo correlation using digoxin as a probe drug. Clin Pharmacol Ther, 2009. 85(2): p. 173-81. 2. Sugimoto, H., et al., Establishment of in vitro P-glycoprotein inhibition assay and its exclusion criteria to assess the risk of drug-drug interaction at the drug discovery stage. J Pharm Sci, 2011. 100(9): p. 4013-23. 3. Zhang, L., et al., A regulatory viewpoint on transporter-based drug interactions. Xenobiotica, 2008. 38(7-8): p. 709-24. 4. Cook, J.A., et al., Refining the in vitro and in vivo critical parameters for P-glycoprotein, [I]/IC50 and [I2]/IC50, that allow for the exclusion of drug candidates from clinical digoxin interaction studies. Mol Pharm, 2010. 7(2): p. 398-411. 5. Tachibana, T., et al., Method for predicting the risk of drug-drug interactions involving inhibition of intestinal CYP3A4 and P-glycoprotein. Xenobiotica, 2009. 39(6): p. 430-43. 6. Vaidyanathan, S., et al., Pharmacokinetics of the oral direct renin inhibitor aliskiren in combination with digoxin, atorvastatin, and ketoconazole in healthy subjects: the role of P- glycoprotein in the disposition of aliskiren. J Clin Pharmacol, 2008. 48(11): p. 1323-38. 7. Verstuyft, C., et al., Dipyridamole enhances digoxin bioavailability via P-glycoprotein inhibition. Clin Pharmacol Ther, 2003. 73(1): p. 51-60. 8. Davy, J.M., et al., Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J, 2008. 156(3): p. 527 e1-9. 9. Pecini, R., et al., Darunavir in Combination With Other Medications: Pharmacokinetic Interactions, in American Conference for the Treatment of HIV (ACTHIV)2007: Dallas, Texas. 10. Shoaf, S.E., et al., In vitro P-glycoprotein interactions and steady-state pharmacokinetic interactions between tolvaptan and digoxin in healthy subjects. J Clin Pharmacol, 2011. 51(5): p. 761-9. 11. Schöller-Gyüre, M., et al., No clinically relevant effect of etravirine (ETR; TMC125) on digoxin pharmacokinetics in HIV-negative volunteers, in 9th International Workshop on Clinical Pharmacology of HIV Therapy2008: New Orleans, LA, USA. 12. Sechaud, R., et al., Absence of an effect of a single-dose deferasirox on the steady-state pharmacokinetics of digoxin. Int J Clin Pharmacol Ther, 2008. 46(10): p. 519-26. 13. Yasui-Furukori, N., et al., Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics. Clin Pharmacol Ther, 2005. 77(1): p. 17-23. 14. Shimizu, M., et al., Effects of itraconazole and diltiazem on the pharmacokinetics of fexofenadine, a substrate of P-glycoprotein. Br J Clin Pharmacol, 2006. 61(5): p. 538-44. 15. Davit, B., et al., FDA evaluations using in vitro metabolism to predict and interpret in vivo metabolic drug-drug interactions: impact on labeling. J Clin Pharmacol, 1999. 39(9): p. 899- 910. 16. Uno, T., et al., Lack of dose-dependent effects of itraconazole on the pharmacokinetic interaction with fexofenadine. Drug Metab Dispos, 2006. 34(11): p. 1875-9. 17. Lemma, G.L., et al., The effect of short- and long-term administration of verapamil on the disposition of cytochrome P450 3A and P-glycoprotein substrates. Clin Pharmacol Ther, 2006. 79(3): p. 218-30. 18. van Heeswijk, R.P., et al., Time-dependent interaction between lopinavir/ritonavir and fexofenadine. J Clin Pharmacol, 2006. 46(7): p. 758-67. 19. Schwarz, U.I., et al., P-glycoprotein inhibitor erythromycin increases oral bioavailability of talinolol in humans. Int J Clin Pharmacol Ther, 2000. 38(4): p. 161-7. 19

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20. Schwarz, U.I., et al., Unexpected effect of verapamil on oral bioavailability of the beta- blocker talinolol in humans. Clin Pharmacol Ther, 1999. 65(3): p. 283-90. 21. Bernsdorf, A., et al., Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms. Br J Clin Pharmacol, 2006. 61(4): p. 440-50. 22. Faessel, H.M., et al., Lack of a pharmacokinetic interaction between a new smoking cessation therapy, varenicline, and digoxin in adult smokers. Eur J Clin Pharmacol, 2008. 64(11): p. 1101-9. 23. Miyakawa, T., et al., The effect of captopril on pharmacokinetics of digoxin in patients with mild congestive heart failure. J Cardiovasc Pharmacol, 1991. 17(4): p. 576-80. 24. Schwartz, J.I., et al., Evaluation of the pharmacokinetics of digoxin in healthy subjects receiving etoricoxib. Br J Clin Pharmacol, 2008. 66(6): p. 811-7. 25. Kirby, B., et al., Simultaneous measurement of in vivo P-glycoprotein and cytochrome P450 3A activities. J Clin Pharmacol, 2006. 46(11): p. 1313-9. 26. Boyd, R.A., et al., Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion. J Clin Pharmacol, 2000. 40(1): p. 91-8. 27. Rodin, S.M., et al., Comparative effects of verapamil and isradipine on steady-state digoxin kinetics. Clin Pharmacol Ther, 1988. 43(6): p. 668-72. 28. Debruyne, D., et al., Nicardipine does not significantly affect serum digoxin concentrations at the steady state of patients with congestive heart failure. Int J Clin Pharmacol Res, 1989. 9(1): p. 15-9. 29. Rapeport, W.G., et al., Absence of a sertraline-mediated effect on digoxin pharmacokinetics and electrocardiographic findings. J Clin Psychiatry, 1996. 57 Suppl 1: p. 16-9. 30. Loi, C.M., et al., Effect of troglitazone on steady-state pharmacokinetics of digoxin. J Clin Pharmacol, 1998. 38(2): p. 178-83. 31. Kirch, W., et al., Dose-dependence of the nifedipine-digoxin interaction? Clin Pharmacol Ther, 1986. 39(1): p. 35-9. 32. Kirch, W., et al., Effect of two different doses of nitrendipine on steady-state plasma digoxin level and systolic time intervals. Eur J Clin Pharmacol, 1986. 31(4): p. 391-5. 33. Rehnqvist, N., et al., Pharmacokinetics of felodipine and effect on digoxin plasma levels in patients with heart failure. Drugs, 1987. 34 Suppl 3: p. 33-42. 34. Baris, N., et al., Influence of carvedilol on serum digoxin levels in heart failure: is there any gender difference? Eur J Clin Pharmacol, 2006. 62(7): p. 535-8. 35. De Mey, C., E. Brendel, and D. Enterling, Carvedilol increases the systemic bioavailability of oral digoxin. Br J Clin Pharmacol, 1990. 29(4): p. 486-90. 36. Stangier, J., et al., Absorption, metabolism, and excretion of intravenously and orally administered [14C]telmisartan in healthy volunteers. J Clin Pharmacol, 2000. 40(12 Pt 1): p. 1312-22. 37. Rameis, H., D. Magometschnigg, and U. Ganzinger, The diltiazem-digoxin interaction. Clin Pharmacol Ther, 1984. 36(2): p. 183-9. 38. Siepmann, M., C. Kleinbloesem, and W. Kirch, The interaction of the calcium antagonist RO 40-5967 with digoxin. Br J Clin Pharmacol, 1995. 39(5): p. 491-6. 39. Kirimli, O., et al., The effects of captopril on serum digoxin levels in patients with severe congestive heart failure. Int J Clin Pharmacol Ther, 2001. 39(7): p. 311-4. 40. Ali, F., et al., Conivaptan: a dual vasopressin receptor v1a/v2 antagonist [corrected]. Cardiovasc Drug Rev, 2007. 25(3): p. 261-79. 41. Mahgoub, A.A., A.H. El-Medany, and A.S. Abdulatif, A comparison between the effects of diltiazem and isosorbide dinitrate on digoxin pharmacodynamics and kinetics in the

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treatment of patients with chronic ischemic heart failure. Saudi Med J, 2002. 23(6): p. 725- 31. 42. Robinson, K., et al., The digoxin-amiodarone interaction. Cardiovasc Drugs Ther, 1989. 3(1): p. 25-8. 43. Schwartz, J.I., et al., Effect of rofecoxib on the pharmacokinetics of digoxin in healthy volunteers. J Clin Pharmacol, 2001. 41(1): p. 107-12. 44. Cook, C.S., L.M. Berry, and E. Burton, Prediction of in vivo drug interactions with eplerenone in man from in vitro metabolic inhibition data. Xenobiotica, 2004. 34(3): p. 215-28. 45. Westphal, K., et al., Oral bioavailability of digoxin is enhanced by talinolol: evidence for involvement of intestinal P-glycoprotein. Clin Pharmacol Ther, 2000. 68(1): p. 6-12. 46. Belz, G.G., et al., Interaction between digoxin and calcium antagonists and antiarrhythmic drugs. Clin. Pharmacol. Ther., 1983. 33(4): p. 410-417. 47. Tsutsumi, K., et al., The effect of erythromycin and clarithromycin on the pharmacokinetics of intravenous digoxin in healthy volunteers. J Clin Pharmacol, 2002. 42(10): p. 1159-64. 48. Larsen, F., M. Priskorn, and K.F. Overo, Lack of citalopram effect on oral digoxin pharmacokinetics. J Clin Pharmacol, 2001. 41(3): p. 340-6. 49. Melia, A.T., et al., The influence of reduced dietary fat absorption induced by orlistat on the pharmacokinetics of digoxin in healthy volunteers. J Clin Pharmacol, 1995. 35(8): p. 840-3. 50. Chien, S.C., et al., Absence of a pharmacokinetic interaction between digoxin and levofloxacin. J Clin Pharm Ther, 2002. 27(1): p. 7-12. 51. Johnson, R.D., et al., Pharmacokinetic interaction of sparfloxacin and digoxin. Clin Ther, 1999. 21(2): p. 368-79. 52. Degner, F.L., et al., The effect of meloxicam on the pharmacokinetics of beta-acetyl-digoxin. Br J Clin Pharmacol, 1995. 40(5): p. 486-8. 53. Hatorp, V. and M.S. Thomsen, Drug interaction studies with repaglinide: repaglinide on digoxin or theophylline pharmacokinetics and cimetidine on repaglinide pharmacokinetics. J Clin Pharmacol, 2000. 40(2): p. 184-92. 54. Depre, M., et al., Effect of multiple doses of montelukast, a CysLT1 receptor antagonist, on digoxin pharmacokinetics in healthy volunteers. J Clin Pharmacol, 1999. 39(9): p. 941-4. 55. Hartmann, M., et al., Lack of interaction between pantoprazole and digoxin at therapeutic doses in man. Int J Clin Pharmacol Ther, 1995. 33(9): p. 481-5. 56. Hager, W.D., et al., Digoxin-quinidine interaction Pharmacokinetic evaluation. N Engl J Med, 1979. 300(22): p. 1238-41. 57. Doering, W., Effect of coadministration of verapamil and quinidine on serum digoxin concentration. Eur J Clin Pharmacol, 1983. 25(4): p. 517-21. 58. Ellens, H., et al., Application of Receiver Operating Characteristic (ROC) Analysis to Refine the Prediction of Potential Digoxin Drug Interactions. Drug Metab Dispos, 2013.