TABLE 1.
Inhibitory effect of 88 compounds on MRP3-mediated E217G transport and MRP4-mediated DHEAS transport, and reported BSEP inhibition
Values in bold indicate that the compounds are defined as MRP3 and MRP4 inhibitors at a concentration of 100 μM based on a cutoff of 19% and 21% for inhibition of MRP3- and MRP4-mediated transport to predict cholestatic potential, respectively.
| Drug | Pharmacology | DILI Type | DILI Severity | MRP3 % Inhibition | MRP4 % Inhibition | BSEP Inhibition | |
|---|---|---|---|---|---|---|---|
| (Mean ± S.D.)a | (Mean ± S.D.)a | IC50 (µM)b | IC50 (µM)c | ||||
| Non-cholestatic BSEP Non-inhibitors | |||||||
| 5-Fluorouracil | Antineoplastic | −d | −6 ± 12 | 1 ± 26 | >135 | ||
| Alprenolol | Antihypertensive | −d | 17 ± 3 | 10 ± 40 | >135 | ||
| Antipyrine | Analgesic/Antipyretic | − | −8 ± 23 | −5 ± 15 | >135 | ||
| Aspirin | NSAID | HCe | 9 ± 11 | 9 ± 42 | >135 | ||
| Caffeine | Stimulant | −d | 3 ± 10 | 5 ± 9 | >135 | ||
| Chlorpheniramine | Antihistamine | −d | 0 ± 7 | 20 ± 10 | >135 | ||
| Clopamide | Diuretic | −d | 6 ± 24 | 10 ± 16 | >135 | ||
| Dexamethasone | Antiinflammatory/Immunosuppressant | −d | −9 ± 9 | 5 ± 34 | 137.4 | >135 | |
| Diphenhydramine | Antihistamine | −d | 7 ± 2 | 31 ± 9 | >135 | ||
| Doxorubicin | Antineoplastic | HCe | −7 ± 19 | 12 ± 12 | >135 | ||
| Etoposide | Antineoplastic | HCe | 107 ± 7 | 33 ± 21 | >135 | ||
| Fluorescein | Diagnostic | −d | 84 ± 17 | 5 ± 10 | >135 | ||
| Metoclopramide | Antiemetic | − f | 3 ± 21 | −12 ± 22 | >135 | ||
| Nadolol | Antianginal/Antihypertensive | −d | 30 ± 9 | −25 ± 24 | >135 | ||
| Naloxone | Opioid antagonist | −d | 9 ± 9 | −7 ± 24 | >135 | ||
| Phenformin | Antidiabetic | −d | 15 ± 9 | 20 ± 50 | >135 | ||
| Probenecid | Antigout agent | HCg | 65 ± 13 | 8 ± 28 | 564.8 | ||
| Quinidine | Antiarrhythmic | HCe | 55 ± 4 | 77 ± 8 | >135 | ||
| Tacrine | Colinesterase inhibitor | HCe | −5 ± 17 | 6 ± 12 | >1000 | >135 | |
| Terbutaline | Sympathicomimetic | −f | −2 ± 11 | 20 ± 8 | >135 | ||
| Theophylline | Antiasthmatic | −g | 13 ± 19 | 4 ± 8 | >135 | ||
| Timolol | Antianginal/Antihypertensive | −d,f | 16 ± 18 | 12 ± 13 | >135 | ||
| Triamterene | Diuretic | −g | −3 ± 27 | 31 ± 21 | >135 | ||
| Vinblastine |
Antineoplastic |
HCe |
85 ± 11 |
10 ± 19 |
>135 |
||
| Cholestatic BSEP Non-inhibitors | |||||||
| Bezafibrate | Antilipemic | Cg | 2 ± 31 | 41 ± 6 | 231.7 | ||
| Carbamazepine | Antiepileptic | Cg | −22 ± 45 | −3 ± 14 | >1000 | ||
| Chloramphenicol | Antibiotic | Ce | 22 ± 20 | 6 ± 25 | >135 | ||
| Chlorpromazine | Antipsychotic | Cg | 77 ± 12 | 84 ± 4 | 147.6 | >135 | |
| Chlorpropamide | Antidiabetic | Ce | 15 ± 15 | −12 ± 44 | >1000 | >135 | |
| Cimetidine | Histamine H2 antagonist | Ce | 0 ± 16 | 0 ± 13 | >135 | ||
| Desipramine | Antidepressant | Ce | 38 ± 27 | 27 ± 9 | >135 | ||
| D-Penicillamine | Antiinflammatory | Cg | 9 ± 8 | −10 ± 13 | >1000 | ||
| Famotidine | Histamine H2 antagonist | Cd | 19 ± 3 | 16 ± 10 | >1000 | >135 | |
| Fluoxetine | Antidepressant | Cf | 69 ± 3 | 70 ± 15 | >135 | ||
| Furosemide | Diuretic | Cd | 29 ± 14 | 109 ± 20 | >1000 | >135 | |
| Haloperidol | Antipsychotic | Ce | 36 ± 10 | 34 ± 32 | >135 | ||
| Ibuprofen | NSAID | Cg | −1 ± 33 | 39 ± 15 | 598.6 | >135 | |
| Maprotiline | Antidepressant | Cg | 40 ± 21 | 29 ± 1 | >135 | ||
| Metformin | Antidiabetic | Cd | BBW | −3 ± 14 | −6 ± 33 | >135 | |
| Nitrofurantoin | Antibiotic | Cg | −7 ± 11 | 101 ± 11 | >1000 | ||
| Nortriptyline | Antidepressant | Ce | 54 ± 20 | 36 ± 10 | >135 | ||
| Promethazine | Antiemetic | C (P.I.) | 29 ± 19 | 64 ± 8 | >135 | ||
| Quinine | Antimalarial | Cg | 7 ± 17 | 41 ± 21 | >135 | ||
| Ranitidine | Histamine H2 antagonist | Ce | 7 ± 5 | 10 ± 10 | >1000 | >135 | |
| Sulfasalazine | Antiinflammatory | Cd | 119 ± 6 | 118 ± 13 | >135 | ||
| Sulindac | NSAID | Ce | 75 ± 13 | 112 ± 9 | 226 | >135 | |
| Tamoxifen | Antiestrogen | Ce | 120 ± 14 | 102 ± 7 | >135 | ||
| Tolbutamide | Antidiabetic | Ce | 38 ± 11 | −5 ± 23 | >1000 | >135 | |
| Trimethoprim | Antibiotic | Ce | 15 ± 17 | 9 ± 17 | >135 | ||
| Verapamil |
Antiarrhythmic |
Ce |
77 ± 11 |
44 ± 7.4 |
>135 |
||
| Non-cholestatic BSEP Inhibitors | |||||||
| Alpidem | Anxiolytic | HCb | Withdrawn | 55 ± 13 | 47 ± 15 | 9.2 | |
| Benzbromarone | Antigout agent | HCd | Withdrawn | 121 ± 8 | 111 ± 4 | 17.5 | |
| Buspirone | Anxiolytic | −d | −9 ± 25 | 13 ± 6 | 104.5 | ||
| Clobetasol propionate | Corticosteroid | −d | 83 ± 10 | 101 ± 23 | 8.5 | ||
| Finasteride | 5α-Reductase inhibitor | −d | 22 ± 5 | 49 ± 8 | 28.2 | ||
| Flupirtine | Nonopioid analgesic agent | HCh | 31 ± 17 | 11 ± 13 | 35.5 | ||
| Glafenine | NSAID | HCe | 59 ± 20 | 105 ± 9 | 22.3 | ||
| Lopinavir | Antiretroviral | HCd | 105 ± 20 | 76 ± 11 | 17.3 | ||
| Mibefradil | Antihypertensive | −d | 95 ± 5 | 91 ± 18 | <135 | ||
| Oxybutynin | Antispasmodic | −d | 51 ± 10 | 67 ± 19 | 27.4 | ||
| Praziquantel | Anthelmintic | −b | −52 ± 11 | 59 ± 16 | 96.8 | ||
| Primaquine | Antiprotozoal | HCe | 35 ± 13 | 11 ± 23 | 32.7 | ||
| Sorafenib | Tyrosine kinase inhibitor | HCd | 114 ± 5 | 121 ± 17 | 8 | ||
| Taxol | Antineoplastic | HCf | 57 ± 38 | 14 ± 26 | 15 | ||
| Tolcapone | COMT inhibitor | HCi | BBW | 101 ± 20 | 113 ± 17 | 119.6 | 34.5 |
| Valinomycin |
Antibiotic |
24 ± 19 |
65 ± 13 |
1.6 |
|||
| Cholestatic BSEP Inhibitors | |||||||
| Acitretin | Antipsoriatic retinoid | Cj | BBW | 4 ± 26 | 33 ± 14 | 18.2 | |
| Clozapine | Antipsychotic | Ce | 30 ± 16 | 25 ± 5 | 126.1 | >135 | |
| Cyclosporin A | Immunosuppressant | Ce | 106 ± 14 | 23 ± 12 | 0.5 | 0.9 | |
| Dicloxacillin | Antibiotic | Cg | 90 ± 9 | 41 ± 18 | 69.7 | <135 | |
| Erythromycin Estolate | Antibiotic | Cg | 2 ± 25 | 79 ± 6 | 4.1 | 13 | |
| Fenofibrate | Antilipemic | Ce | 5 ± 8 | 39 ± 3 | 15.3 | ||
| Fluvastatin | Antilipemic | Cd | 93 ± 11 | 62 ± 2 | 36.1 | ||
| Glyburide | Antidiabetic | Ce | 98 ± 4 | 93 ± 1 | 5.3 | 6.1 | |
| Indinavir | Antiretroviral | Cd | 75 ± 7 | 15 ± 24 | 21.2 | ||
| Indomethacin | NSAID | Ce | 64 ± 2 | 111 ± 18 | 42 | ||
| Nifedipine | Antianginal, antihypertensive | Cg | 32 ± 14 | 46 ± 6 | 30.7 | ||
| Nitrendipine | Antihypertensive | Cd | 45 ± 11 | 93 ± 11 | <135 | ||
| 19-Norethindrone | Contraceptive | Cd | 18 ± 14 | 33 ± 19 | <135 | ||
| Omeprazole | Proton pump inhibitor | Cd | 12 ± 16 | 21 ± 17 | <135 | ||
| Pioglitazone | Antidiabetic | Ck | −116 ± 48 | 34 ± 16 | 0.3 | 0.3 | |
| Rifampicin | Antibiotic | Cg | 93 ± 15 | 60 ± 14 | 11.3 | 25.3 | |
| Rifamycin SV | Antibiotic | Cg | 111 ± 6 | 75 ± 9 | 6.3 | ||
| Ritonavir | Antiretroviral | Cd | 112 ± 6 | 72 ± 3 | 2.2 | ||
| Rosiglitazone | Antidiabetic | Ck | −44 ± 9 | 88 ± 10 | 6.4 | 4.4 | |
| Simvastatin | Antilipemic | Cg | 122 ± 5 | 111 ± 8 | 24.7 | ||
| Ticlopidine | Antiplatelet | Cg | −45 ± 34 | 35 ± 12 | 74 | ||
| Troglitazone | Antidiabetic | Cl | Withdrawn | 121 ± 4 | 105 ± 5 | 2.7 | 5.9 |
BBW, black box warning; C, cholestatic; COMT, catechol-O-methyl transferase; HC, hepatocellular; NSAID, nonsteroidal anti-inflammatory drug; P.I., package insert; −, no reports of liver injury.
a
Control is defined as uptake in presence of 1% DMSO, no inhibitor (100% transport).
d
Micromedex.
f
Lexicomp.