The ABC transporter affinities of the 123 compounds in this study
Experimentally determined inhibition of BCRP-mediated mitoxantrone efflux and important molecular descriptors are shown for the compounds in this study, along with data from the literature on the affinity for P-gp, MRP1, and MRP2 obtained from the University of Tokyo transporter database (Ozawa et al., 2004).
Substance | Mitoxantrone Accumulationa | Molecular Polarizability | logD7.4 | ABCB1 P-gpb | ABCC1 MRP1b | ABCC2 MRP2b |
|---|---|---|---|---|---|---|
| -Fold increase | ||||||
| Compounds previously reported as BCRP substrates or inhibitors | ||||||
| Chrysin*c | 8.4 | 26 | 2.8 | — | Y | — |
| Gefitinib*c,d | 8.0 | 47 | 4.4 | Y | — | — |
| Imatinib mesylatec,d | 8.0 | 58 | 2.4 | Y | — | — |
| Ko143c | 8.0 | 54 | 3.6 | — | — | — |
| Fumitremorgin C*c | 7.9 | 44 | 2.2 | — | — | — |
| Diethylstilbestrolc | 7.7 | 34 | 4.6 | Y | — | — |
| GF120918 (Elacridar)c | 7.7 | 64 | 4.6 | Y | N | N |
| Cyclosporine-A*c | 6.4 | 143 | 4.5 | Y | Y | Y |
| Prazosin*d | 5.7 | 40 | 1.6 | Y | — | — |
| Saquinavirc | 5.7 | 79 | 4.6 | Y | Y | — |
| Ritonavir*c | 5.1 | 83 | 4.3 | Y | Y | — |
| β-Estradiolcd | 5.1 | 35 | 3.6 | Y | — | — |
| Verapamil*c | 4.1 | 56 | 3.7 | Y | Y | Y |
| Tamoxifend | 3.8 | 49 | 5.0 | Y | — | — |
| Hoechst 33342d | 3.7 | 53 | 3.1 | Y | — | — |
| Quercetin*c | 3.3 | 27 | 1.0 | Y | Y | — |
| Omeprazolec | 3.1 | 38 | 1.6 | Y | — | — |
| Methotrexate*d | 1.5 | 44 | -4.8 | Y | Y | Y |
| Compounds with a previously unknown BCRP affinity but with a reported affinity for other major ABC transporters | ||||||
| Ergocristine*e | 9.1 | 70 | 4.4 | Y | — | — |
| Nicardipinee | 8.1 | 53 | 4.4 | Y | — | — |
| Ethinylestradiole | 8.0 | 38 | 3.7 | Y | — | — |
| Astemizolee | 7.8 | 55 | 5.4 | Y | — | — |
| Felodipinee | 7.5 | 39 | 4.9 | Y | — | — |
| Glibenclamidee | 7.4 | 53 | 2.7 | Y | Y | Y |
| Ketoconazolee | 6.6 | 56 | 4.1 | Y | — | — |
| Chlorprotixene*e | 6.5 | 38 | 4.3 | Y | — | — |
| Nitrendipinee | 6.3 | 37 | 3.4 | Y | — | — |
| Chlorpromazinee | 5.4 | 38 | 3.9 | Y | — | — |
| Progesteronee | 4.9 | 42 | 3.9 | Y | — | — |
| Mifepristonee | 4.7 | 56 | 4.9 | Y | Y | — |
| Dipyridamole*c,d,e,f | 4.6 | 57 | 1.5 | Y | — | — |
| Lopinavire | 3.9 | 76 | 5.2 | Y | — | — |
| Amiodaronee | 3.9 | 58 | 4.8 | Y | — | — |
| Simvastatine | 3.9 | 52 | 4.6 | Y | — | Y |
| Loperamidee | 3.7 | 58 | 4.8 | Y | — | — |
| Terfenadine*e | 3.0 | 62 | 5.9 | Y | — | — |
| Clotrimazole | 3.0 | 41 | 5.0 | Y | — | — |
| Spironolactone* | 2.6 | 51 | 2.9 | Y | — | — |
| Maprotiline* | 2.3 | 38 | 2.3 | Y | — | — |
| Digoxin* | 2.0 | 87 | 2.4 | Y | — | — |
| Quinine | 2.0 | 40 | 2.4 | Y | — | — |
| Fexofenadine* | 1.9 | 62 | 2.4 | Y | — | — |
| Diltiazem* | 1.4 | 47 | 2.4 | Y | — | — |
| Erythromycin* | 1.4 | 83 | 3.1 | Y | Y | — |
| Etoposide | 1.3 | 58 | 0.3 | Y | Y | Y |
| Prednisone* | 1.2 | 41 | 1.6 | Y | — | — |
| Trimethoprim | 1.2 | 31 | 1.3 | Y | — | — |
| Chlorzoxazone* | 1.2 | 15 | 1.8 | Y | — | — |
| Folic acid | 1.2 | 42 | -5.4 | — | — | Y |
| Lansoprazol | 1.2 | 35 | 2.0 | Y | — | — |
| Ranitidine | 1.1 | 34 | 0.7 | Y | — | — |
| Cimetidine*d,f | 1.1 | 28 | 0.2 | Y | — | — |
| Indomethacin | 1.1 | 37 | 0.2 | N | Y | Y |
| Prednisolone | 1.1 | 42 | 1.5 | Y | — | — |
| Propranolol | 1.0 | 32 | 1.2 | Y | — | — |
| Timolol | 0.9 | 35 | 0.2 | Y | — | — |
| Desipramine | 0.9 | 35 | 1.8 | Y | — | — |
| Pravastatin | 0.8 | 49 | 0.4 | Y | — | Y |
| Hydrocortisone | 0.8 | 43 | 1.6 | Y | — | — |
| Sulfinpyrazone | 0.8 | 46 | -1.2 | N | Y | Y |
| Compounds with no previously reported ABC transporter affinity | ||||||
| Fenofibrate*e | 7.9 | 40 | 5.0 | — | — | — |
| Tipranavir*e | 7.4 | 64 | 5.0 | — | — | |
| Erlotinib*e | 7.2 | 43 | 3.3 | — | — | — |
| Flupentixol*e | 6.1 | 47 | 3.7 | — | — | — |
| Celecoxibe | 5.6 | 36 | 3.4 | — | — | — |
| Thioridazinee | 4.5 | 47 | 4.5 | — | — | — |
| Isradipinee | 4.1 | 39 | 3.3 | — | — | — |
| Fendiline*e | 4.1 | 43 | 3.6 | — | — | — |
| Medroxyprogesterone*e | 3.9 | 44 | 3.5 | — | — | — |
| Pramoxinee | 3.0 | 36 | 2.7 | — | — | — |
| Piroxicam* | 2.7 | 33 | 0.2 | — | — | — |
| Terazosin | 2.4 | 42 | 1.6 | — | — | — |
| Diazoxide | 2.0 | 22 | -1.0 | — | — | — |
| Oxazepam* | 1.9 | 30 | 2.3 | — | — | — |
| Propafenone* | 1.9 | 42 | 1.6 | — | — | — |
| Tinidazole | 1.9 | 24 | -0.4 | — | — | — |
| Meclizine* | 1.7 | 49 | 4.9 | — | — | — |
| Tetracycline* | 1.6 | 45 | -2.6 | — | — | — |
| Budesonide | 1.5 | 50 | 2.3 | — | — | — |
| Desmethyldiazepam | 1.5 | 29 | 2.5 | N | — | — |
| Nevirapine | 1.5 | 30 | 1.4 | — | — | — |
| Diazepam | 1.4 | 31 | 2.9 | N | — | — |
| Zanamivir* | 1.4 | 30 | -5.4 | — | — | — |
| Flurbiprofen* | 1.4 | 27 | 0.8 | — | — | — |
| Neomycin sulfate | 1.3 | 32 | -7.6 | — | — | — |
| Nitrofurantoin*d,f | 1.4 | 19 | -0.6 | — | — | — |
| Valacyclovir | 1.4 | 32 | -3.1 | — | — | — |
| Carbamazepine | 1.3 | 28 | 2.4 | N | — | — |
| Chenodeoxycholic acid | 1.3 | 51 | 2.7 | — | — | — |
| Hydrochlorothiazide | 1.3 | 26 | -0.3 | — | — | — |
| Amantadine* | 1.2 | 21 | -0.4 | N | — | — |
| Amoxicillin | 1.2 | 37 | -4.6 | — | — | — |
| Phenytoin | 1.2 | 28 | 2.1 | — | — | — |
| Antipyrine | 1.2 | 22 | 1.3 | — | — | — |
| Bendroflumethiazide | 1.1 | 38 | 1.7 | — | — | — |
| Ganciclovir | 1.1 | 23 | -4.2 | — | — | — |
| Metoclopramide* | 1.1 | 33 | 0.9 | — | — | — |
| Pindolol | 1.1 | 30 | 0.0 | — | — | — |
| Warfarin | 1.1 | 34 | 1.1 | — | — | — |
| Amiloride | 1.1 | 19 | -3.3 | — | — | — |
| Bupivacaine | 1.0 | 38 | 3.4 | — | — | — |
| Carisoprodol | 1.1 | 29 | 1.7 | — | — | — |
| Nizatidine | 1.1 | 36 | 0.7 | — | — | — |
| Orphenadrine* | 1.1 | 35 | 2.6 | — | — | — |
| Procyclidine | 1.1 | 39 | 2.6 | — | — | — |
| Acyclovir | 1.0 | 20 | -1.3 | — | — | — |
| Atropine | 1.0 | 35 | 0.8 | — | — | — |
| Captopril* | 1.0 | 23 | -2.2 | N | — | — |
| Furosemide* | 1.0 | 30 | -0.8 | — | — | — |
| Hydralazine | 1.0 | 17 | 0.6 | — | — | — |
| Levothyroxine | 1.0 | 47 | 0.6 | — | — | — |
| Salicylic acid | 1.0 | 13 | -1.5 | — | — | — |
| Sotalol | 1.0 | 31 | -1.5 | — | — | — |
| Valganciclovir | 1.0 | 35 | -3.5 | — | — | — |
| Levodopa | 0.9 | 19 | -4.6 | — | — | — |
| Methimazole* | 0.9 | 12 | 0.0 | — | — | — |
| Sulindac | 1.0 | 39 | 0.3 | — | — | — |
| Metoprolol | 0.8 | 33 | 0.2 | N | — | — |
| Zidovudine | 0.9 | 24 | -0.2 | — | — | — |
| Gliclazide | 0.8 | 36 | -0.2 | — | — | — |
| Mesalazine | 0.6 | 14 | -2.0 | — | — | — |
| Bupropion | 0.5 | 29 | 2.1 | — | — | — |
| Sulfasalazine*d,f | 0.4 | 39 | 0.0 | — | — | — |
↵* Test set compounds.
↵ a Expressed as the ratio of the mitoxantrone accumulation after coincubation with inhibitor to that observed in cells incubated with mitoxantrone only. A more than 3-fold increase was used as a cut-off for significant BCRP inhibition. The accumulation ratios were normalized to that obtained with the potent inhibitor Ko143 (100% inhibition) to account for interday variability. Ko143 and Fumitremorgin C were tested at 0.5 μM and GF120918 at 10 μM. All other compounds were tested at 50 μM.
↵ b Y, compounds with an affinity for the transporter, according to the literature; N, compounds for which a lack of affinity for the transporter has been reported in the literature; —, compounds for which no data are available in the literature.
↵ c This compound has previously been reported to be an inhibitor of BCRP.
↵ d This compound has previously been reported to be a BCRP substrate.
↵ e This compound has not previously been reported to be a BCRP inhibitor.
↵ f During the course of this study, it was reported that cimetidine, nitrofurantoin (Jonker et al., 2005), dipyridamole (Zhang et al., 2005), and sulfasalazine (Zaher et al., 2006) were BCRP substrates in independent publications.