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.

DrugPharmacologyDILI TypeDILI SeverityMRP3 % InhibitionMRP4 % InhibitionBSEP Inhibition
(Mean ± S.D.)a(Mean ± S.D.)aIC50
(µM)bIC50
(µM)c
Non-cholestatic BSEP Non-inhibitors
5-FluorouracilAntineoplasticd−6 ± 121 ± 26>135
AlprenololAntihypertensived17 ± 310 ± 40>135
AntipyrineAnalgesic/Antipyretic−8 ± 23−5 ± 15>135
AspirinNSAIDHCe9 ± 119 ± 42>135
CaffeineStimulantd3 ± 105 ± 9>135
ChlorpheniramineAntihistamined0 ± 720 ± 10>135
ClopamideDiureticd6 ± 2410 ± 16>135
DexamethasoneAntiinflammatory/Immunosuppressantd−9 ± 95 ± 34137.4>135
DiphenhydramineAntihistamined7 ± 231 ± 9>135
DoxorubicinAntineoplasticHCe−7 ± 1912 ± 12>135
EtoposideAntineoplasticHCe107 ± 733 ± 21>135
FluoresceinDiagnosticd84 ± 175 ± 10>135
MetoclopramideAntiemeticf3 ± 21−12 ± 22>135
NadololAntianginal/Antihypertensived30 ± 9−25 ± 24>135
NaloxoneOpioid antagonistd9 ± 9−7 ± 24>135
PhenforminAntidiabeticd15 ± 920 ± 50>135
ProbenecidAntigout agentHCg65 ± 138 ± 28564.8
QuinidineAntiarrhythmicHCe55 ± 477 ± 8>135
TacrineColinesterase inhibitorHCe−5 ± 176 ± 12>1000>135
TerbutalineSympathicomimeticf−2 ± 1120 ± 8>135
TheophyllineAntiasthmaticg13 ± 194 ± 8>135
TimololAntianginal/Antihypertensived,f16 ± 1812 ± 13>135
TriamtereneDiureticg−3 ± 2731 ± 21>135
VinblastineAntineoplasticHCe85 ± 1110 ± 19>135
Cholestatic BSEP Non-inhibitors
BezafibrateAntilipemicCg2 ± 3141 ± 6231.7
CarbamazepineAntiepilepticCg−22 ± 45−3 ± 14>1000
ChloramphenicolAntibioticCe22 ± 206 ± 25>135
ChlorpromazineAntipsychoticCg77 ± 1284 ± 4147.6>135
ChlorpropamideAntidiabeticCe15 ± 15−12 ± 44>1000>135
CimetidineHistamine H2 antagonistCe0 ± 160 ± 13>135
DesipramineAntidepressantCe38 ± 2727 ± 9>135
D-PenicillamineAntiinflammatoryCg9 ± 8−10 ± 13>1000
FamotidineHistamine H2 antagonistCd19 ± 316 ± 10>1000>135
FluoxetineAntidepressantCf69 ± 370 ± 15>135
FurosemideDiureticCd29 ± 14109 ± 20>1000>135
HaloperidolAntipsychoticCe36 ± 1034 ± 32>135
IbuprofenNSAIDCg−1 ± 3339 ± 15598.6>135
MaprotilineAntidepressantCg40 ± 2129 ± 1>135
MetforminAntidiabeticCdBBW−3 ± 14−6 ± 33>135
NitrofurantoinAntibioticCg−7 ± 11101 ± 11>1000
NortriptylineAntidepressantCe54 ± 2036 ± 10>135
PromethazineAntiemeticC (P.I.)29 ± 1964 ± 8>135
QuinineAntimalarialCg7 ± 1741 ± 21>135
RanitidineHistamine H2 antagonistCe7 ± 510 ± 10>1000>135
SulfasalazineAntiinflammatoryCd119 ± 6118 ± 13>135
SulindacNSAIDCe75 ± 13112 ± 9226>135
TamoxifenAntiestrogenCe120 ± 14102 ± 7>135
TolbutamideAntidiabeticCe38 ± 11−5 ± 23>1000>135
TrimethoprimAntibioticCe15 ± 179 ± 17>135
VerapamilAntiarrhythmicCe77 ± 1144 ± 7.4>135
Non-cholestatic BSEP Inhibitors
AlpidemAnxiolyticHCbWithdrawn55 ± 1347 ± 159.2
BenzbromaroneAntigout agentHCdWithdrawn121 ± 8111 ± 417.5
BuspironeAnxiolyticd−9 ± 2513 ± 6104.5
Clobetasol propionateCorticosteroidd83 ± 10101 ± 238.5
Finasteride5α-Reductase inhibitord22 ± 549 ± 828.2
FlupirtineNonopioid analgesic agentHCh31 ± 1711 ± 1335.5
GlafenineNSAIDHCe59 ± 20105 ± 922.3
LopinavirAntiretroviralHCd105 ± 2076 ± 1117.3
MibefradilAntihypertensived95 ± 591 ± 18<135
OxybutyninAntispasmodicd51 ± 1067 ± 1927.4
PraziquantelAnthelminticb−52 ± 1159 ± 1696.8
PrimaquineAntiprotozoalHCe35 ± 1311 ± 2332.7
SorafenibTyrosine kinase inhibitorHCd114 ± 5121 ± 178
TaxolAntineoplasticHCf57 ± 3814 ± 2615
TolcaponeCOMT inhibitorHCiBBW101 ± 20113 ± 17119.634.5
ValinomycinAntibiotic24 ± 1965 ± 131.6
Cholestatic BSEP Inhibitors
AcitretinAntipsoriatic retinoidCjBBW4 ± 2633 ± 1418.2
ClozapineAntipsychoticCe30 ± 1625 ± 5126.1>135
Cyclosporin AImmunosuppressantCe106 ± 1423 ± 120.50.9
DicloxacillinAntibioticCg90 ± 941 ± 1869.7<135
Erythromycin EstolateAntibioticCg2 ± 2579 ± 64.113
FenofibrateAntilipemicCe5 ± 839 ± 315.3
FluvastatinAntilipemicCd93 ± 1162 ± 236.1
GlyburideAntidiabeticCe98 ± 493 ± 15.36.1
IndinavirAntiretroviralCd75 ± 715 ± 2421.2
IndomethacinNSAIDCe64 ± 2111 ± 1842
NifedipineAntianginal, antihypertensiveCg32 ± 1446 ± 630.7
NitrendipineAntihypertensiveCd45 ± 1193 ± 11<135
19-NorethindroneContraceptiveCd18 ± 1433 ± 19<135
OmeprazoleProton pump inhibitorCd12 ± 1621 ± 17<135
PioglitazoneAntidiabeticCk−116 ± 4834 ± 160.30.3
RifampicinAntibioticCg93 ± 1560 ± 1411.325.3
Rifamycin SVAntibioticCg111 ± 675 ± 96.3
RitonavirAntiretroviralCd112 ± 672 ± 32.2
RosiglitazoneAntidiabeticCk−44 ± 988 ± 106.44.4
SimvastatinAntilipemicCg122 ± 5111 ± 824.7
TiclopidineAntiplateletCg−45 ± 3435 ± 1274
TroglitazoneAntidiabeticClWithdrawn121 ± 4105 ± 52.75.9
  • 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).

  • b Dawson et al., 2012.

  • c Morgan et al., 2010.

  • d Micromedex.

  • e Zimmerman, 1999.

  • f Lexicomp.

  • g Stricker, 1992.

  • h Puls et al., 2011.

  • i Mayoral et al. 1999.

  • j Kreiss et al., 2002.

  • k Floyd et al., 2009.

  • l Kaplowitz and DeLeve, 2007.