Initial Set of Compounds Used for the Identification and Refinement of the In Vitro Bioactivation Liver Response Assay (BA-LRA) Signature
| Compound . | Clinical DILI Risk . | Potential DILI Mechanisms . | In Vivo Rat BA-LRA DILI Prediction . | Rat HEPATOPAC In Vitro BA-LRA Scores (> 0.20) . | Reference . |
|---|---|---|---|---|---|
| Amiodarone | DILI+ve | Mitochondrial/lysosomal toxicity | Negative | Negative up to 30 µM | LiverTox database |
| Benzbromarone | DILI+ve | Mitochondrial toxicity; BSEP inhibition | Insufficiently tested | Negative up to 30 µM | Hafey et al., (unpublished data) and LiverTox database |
| Diclofenac | DILI+ve | Multifactorial/immune mediated | Insufficiently tested | Positive @ 200 µM | LiverTox database |
| Flutamide | DILI+ve | Reactive metabolite | Positive | Positive @ 50 µM | LiverTox database |
| Isoniazid | DILI+ve | Reactive metabolite/immune mediated | Insufficiently tested | Negative up to 1000 µM | LiverTox database |
| MK-3207 | DILI+ve | Reactive metabolite | Positive | Positive @ 30 µM | Hargreaves and Olesen (2019) and Monroe et al. (2020) |
| MK-0974 | DILI+ve | Reactive metabolite | Underestimated signal/insufficiently tested | Positive @ 30 µM | Hargreaves and Olesen (2019) and Monroe et al. (2020) |
| Sitaxsentan | DILI+ve | Bile salt accumulation/reactive metabolite | Positive | Positive @ 100 µM | Kenna et al. (2015) |
| Ticlopidine | DILI+ve | Reactive metabolite | Positive | Positive @ 30 µM | LiverTox database |
| Zafirlukast | DILI+ve | Reactive metabolite/BSEP inhibition | Negative | Negative up to 30 µM | LiverTox database |
| Clarithromycin | DILI−ve | N/A | Positive | Negative up to 30 µM | Monroe et al. (2020) |
| Warfarin | DILI−ve | N/A | Not tested | Negative up to 80 µM | LiverTox database |
| Bardoxolone | N/A | N/A | Positive | Positive @ 0.2 µM | N/A |
| β-Naphthoflavone | N/A | N/A | Not tested | Positive @ 30 µM | N/A |
| Compound . | Clinical DILI Risk . | Potential DILI Mechanisms . | In Vivo Rat BA-LRA DILI Prediction . | Rat HEPATOPAC In Vitro BA-LRA Scores (> 0.20) . | Reference . |
|---|---|---|---|---|---|
| Amiodarone | DILI+ve | Mitochondrial/lysosomal toxicity | Negative | Negative up to 30 µM | LiverTox database |
| Benzbromarone | DILI+ve | Mitochondrial toxicity; BSEP inhibition | Insufficiently tested | Negative up to 30 µM | Hafey et al., (unpublished data) and LiverTox database |
| Diclofenac | DILI+ve | Multifactorial/immune mediated | Insufficiently tested | Positive @ 200 µM | LiverTox database |
| Flutamide | DILI+ve | Reactive metabolite | Positive | Positive @ 50 µM | LiverTox database |
| Isoniazid | DILI+ve | Reactive metabolite/immune mediated | Insufficiently tested | Negative up to 1000 µM | LiverTox database |
| MK-3207 | DILI+ve | Reactive metabolite | Positive | Positive @ 30 µM | Hargreaves and Olesen (2019) and Monroe et al. (2020) |
| MK-0974 | DILI+ve | Reactive metabolite | Underestimated signal/insufficiently tested | Positive @ 30 µM | Hargreaves and Olesen (2019) and Monroe et al. (2020) |
| Sitaxsentan | DILI+ve | Bile salt accumulation/reactive metabolite | Positive | Positive @ 100 µM | Kenna et al. (2015) |
| Ticlopidine | DILI+ve | Reactive metabolite | Positive | Positive @ 30 µM | LiverTox database |
| Zafirlukast | DILI+ve | Reactive metabolite/BSEP inhibition | Negative | Negative up to 30 µM | LiverTox database |
| Clarithromycin | DILI−ve | N/A | Positive | Negative up to 30 µM | Monroe et al. (2020) |
| Warfarin | DILI−ve | N/A | Not tested | Negative up to 80 µM | LiverTox database |
| Bardoxolone | N/A | N/A | Positive | Positive @ 0.2 µM | N/A |
| β-Naphthoflavone | N/A | N/A | Not tested | Positive @ 30 µM | N/A |
Abbreviations: DILI, drug-induced liver injury; N/A, not applicable. LiverTox database: available at https://www.ncbi.nlm.nih.gov/books/NBK547852, last accessed April 8, 2020.
Initial Set of Compounds Used for the Identification and Refinement of the In Vitro Bioactivation Liver Response Assay (BA-LRA) Signature
| Compound . | Clinical DILI Risk . | Potential DILI Mechanisms . | In Vivo Rat BA-LRA DILI Prediction . | Rat HEPATOPAC In Vitro BA-LRA Scores (> 0.20) . | Reference . |
|---|---|---|---|---|---|
| Amiodarone | DILI+ve | Mitochondrial/lysosomal toxicity | Negative | Negative up to 30 µM | LiverTox database |
| Benzbromarone | DILI+ve | Mitochondrial toxicity; BSEP inhibition | Insufficiently tested | Negative up to 30 µM | Hafey et al., (unpublished data) and LiverTox database |
| Diclofenac | DILI+ve | Multifactorial/immune mediated | Insufficiently tested | Positive @ 200 µM | LiverTox database |
| Flutamide | DILI+ve | Reactive metabolite | Positive | Positive @ 50 µM | LiverTox database |
| Isoniazid | DILI+ve | Reactive metabolite/immune mediated | Insufficiently tested | Negative up to 1000 µM | LiverTox database |
| MK-3207 | DILI+ve | Reactive metabolite | Positive | Positive @ 30 µM | Hargreaves and Olesen (2019) and Monroe et al. (2020) |
| MK-0974 | DILI+ve | Reactive metabolite | Underestimated signal/insufficiently tested | Positive @ 30 µM | Hargreaves and Olesen (2019) and Monroe et al. (2020) |
| Sitaxsentan | DILI+ve | Bile salt accumulation/reactive metabolite | Positive | Positive @ 100 µM | Kenna et al. (2015) |
| Ticlopidine | DILI+ve | Reactive metabolite | Positive | Positive @ 30 µM | LiverTox database |
| Zafirlukast | DILI+ve | Reactive metabolite/BSEP inhibition | Negative | Negative up to 30 µM | LiverTox database |
| Clarithromycin | DILI−ve | N/A | Positive | Negative up to 30 µM | Monroe et al. (2020) |
| Warfarin | DILI−ve | N/A | Not tested | Negative up to 80 µM | LiverTox database |
| Bardoxolone | N/A | N/A | Positive | Positive @ 0.2 µM | N/A |
| β-Naphthoflavone | N/A | N/A | Not tested | Positive @ 30 µM | N/A |
| Compound . | Clinical DILI Risk . | Potential DILI Mechanisms . | In Vivo Rat BA-LRA DILI Prediction . | Rat HEPATOPAC In Vitro BA-LRA Scores (> 0.20) . | Reference . |
|---|---|---|---|---|---|
| Amiodarone | DILI+ve | Mitochondrial/lysosomal toxicity | Negative | Negative up to 30 µM | LiverTox database |
| Benzbromarone | DILI+ve | Mitochondrial toxicity; BSEP inhibition | Insufficiently tested | Negative up to 30 µM | Hafey et al., (unpublished data) and LiverTox database |
| Diclofenac | DILI+ve | Multifactorial/immune mediated | Insufficiently tested | Positive @ 200 µM | LiverTox database |
| Flutamide | DILI+ve | Reactive metabolite | Positive | Positive @ 50 µM | LiverTox database |
| Isoniazid | DILI+ve | Reactive metabolite/immune mediated | Insufficiently tested | Negative up to 1000 µM | LiverTox database |
| MK-3207 | DILI+ve | Reactive metabolite | Positive | Positive @ 30 µM | Hargreaves and Olesen (2019) and Monroe et al. (2020) |
| MK-0974 | DILI+ve | Reactive metabolite | Underestimated signal/insufficiently tested | Positive @ 30 µM | Hargreaves and Olesen (2019) and Monroe et al. (2020) |
| Sitaxsentan | DILI+ve | Bile salt accumulation/reactive metabolite | Positive | Positive @ 100 µM | Kenna et al. (2015) |
| Ticlopidine | DILI+ve | Reactive metabolite | Positive | Positive @ 30 µM | LiverTox database |
| Zafirlukast | DILI+ve | Reactive metabolite/BSEP inhibition | Negative | Negative up to 30 µM | LiverTox database |
| Clarithromycin | DILI−ve | N/A | Positive | Negative up to 30 µM | Monroe et al. (2020) |
| Warfarin | DILI−ve | N/A | Not tested | Negative up to 80 µM | LiverTox database |
| Bardoxolone | N/A | N/A | Positive | Positive @ 0.2 µM | N/A |
| β-Naphthoflavone | N/A | N/A | Not tested | Positive @ 30 µM | N/A |
Abbreviations: DILI, drug-induced liver injury; N/A, not applicable. LiverTox database: available at https://www.ncbi.nlm.nih.gov/books/NBK547852, last accessed April 8, 2020.
This PDF is available to Subscribers Only
View Article Abstract & Purchase OptionsFor full access to this pdf, sign in to an existing account, or purchase an annual subscription.
