Liu et al.: In Vitro to In Vivo Extrapolation for Drug-Induced Liver Injury Using a Pair Ranking Method Supplementary Data Tab. S1: The standard study protocol of TG-GATEs Assays Species Tissues Number of Treatment Dose/ Abbreviation compounds* concentration** In vitro Human primary 120 2, 8, 24 h Low, middle, InVitro_Human hepatocytes high (1:5:25) Sprague-Dawley primary 131 2, 8, 24 h Low, middle, InVitro_Rat rat (6 weeks old) hepatocytes high (1:5:25) In vivo Sprague-Dawley liver 131 24 h after Low, middle, InVivo rat (6 weeks old) the last dose of high repeated (mainly 1:3:10) administration for 3, 7, 14 and 28 days * There are a total of 170 compounds in the Open TG-GATEs database. In this study, only 131 compounds, which were generated in the first phase of TG-GATEs, were employed. ** For the in vivo assay, the highest dose was chosen to match the level that induces the minimum toxic effect in a 4-week toxicity study. Then, the ratio of the low, middle and high dose levels was set as 1:3:10. For the in vitro assay, the highest concentration was defined as the dose level generating an 80-90% relative survival ratio with a ratio of 1:5:25 for the low, middle and high concentration levels. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is appropriately cited. doi.org/10.14573/altex.1610201s ALTEX 34(3), SUPPLEMENTARY DATA S1 LIU ET AL. Tab. S2: Drug-induced liver injury endpoints Categories Number of Compound names compounds Drug induced liver injury (DILI) Most DILI concern 46 Amitriptyline; coumarin; diltiazem; ethanol; hydroxyzine; tetracycline; vitamin A; acarbose; allyl alcohol; benzbromarone; bucetin; carbamazepine; chlormadinone; chlormezanone; chlorpheniramine; cimetidine; ciprofloxacin; clofibrate; cyclosporine A; danazol; ethambutol; fluphenazine; griseofulvin; haloperidol; hexachlorobenzene; ibuprofen; mefenamic acid; metformin; methyldopa; methyltestosterone; moxisylyte; nicotinic acid; nifedipine; nitrofurazone; omeprazole; pemoline; phenylanthranilic acid; phenytoin; quinidine; rifampicin; simvastatin; sulindac; sulpiride; tamoxifen; thioridazine; trimethadione Xu’s label 47 Acetaminophen; acetazolamide; allopurinol; amiodarone; azathioprine; benzbromarone; captopril; chloramphenicol; chlorpheniramine; ciprofloxacin; clomipramine; cyclophosphamide; cyclosporine A; danazol; dantrolene; diclofenac; disopyramide; erythromycin ethylsuccinate; ethionine; etoposide; fenofibrate; flutamide; furosemide; gemfibrozil; griseofulvin; imipramine; isoniazid; labetalol; mefenamic acid; methimazole; mexiletine; nicotinic acid; nifedipine; nimesulide; perhexiline; phenacetin; phenylbutazone; phenytoin; quinidine; sulfasalazine; sulindac; tamoxifen; tetracycline; thioacetamide; ticlopidine; trimethadione; vitamin A Sakatis’s label 51 Amitriptyline; tacrine; cimetidine; ranitidine; amiodarone; danazol; labetalol; nimesulide; acetaminophen; diclofenac; flutamide; azathioprine; tamoxifen; cyclophosphamide; erythromycin ethylsuccinate; benzbromarone; nifedipine; imipramine; nicotinic acid; dantrolene; isoniazid; sulindac; ketoconazole; methyldopa; nitrofurantoin; valproic acid; cyclosporine A; etoposide; phenylbutazone; disulfiram; propylthiouracil; ibuprofen; rifampicin; fenofibrate; furosemide; quinidine; tetracycline; doxorubicin; ciprofloxacin; mefenamic acid; perhexiline; ticlopidine; chlorpropamide; iproniazid; sulfasalazine; allopurinol; phenytoin; carbamazepine; coumarin; phenobarbital; sulpiride Hepatic failure 24 Acetazolamide; allopurinol; amitriptyline; azathioprine; carbamazepine; ciprofloxacin; dantrolene; diclofenac; disulfiram; doxorubicin; glibenclamide; ibuprofen; mefenamic acid; omeprazole; propylthiouracil; ranitidine; simvastatin; sulfasalazine; sulindac; terbinafine; tetracycline; ticlopidine; triazolam; valproic acid Other hepatotoxic endpoints Biochemical parameters AST increased 13 Acetaminophen; amiodarone; carboplatin; ciprofloxacin; colchicine; diclofenac; diltiazem; fenofibrate; flutamide; nitrofurantoin; omeprazole; tamoxifen; valproic acid ALT increased 9 Amiodarone; ciprofloxacin; colchicine; diclofenac; fenofibrate; nitrofurantoin; omeprazole; ticlopidine; valproic acid Hepatic enzyme increased 8 Acarbose; diclofenac; disopyramide; furosemide; ibuprofen; mefenamic acid; terbinafine; valproic acid Blood bilirubin increased 6 Carboplatin; ciprofloxacin; doxorubicin; fenofibrate; gemfibrozil; tamoxifen Liver injury patterns Cholestasis 7 Captopril; glibenclamide; ibuprofen; nifedipine; sulindac; tamoxifen; thioridazine Hepatocellular injury 16 Acarbose; amiodarone; azathioprine; captopril; ciprofloxacin; colchicine; fluphenazine; isoniazid; methyldopa; omeprazole; phenobarbital; phenytoin; ranitidine; sulfasalazine; terbinafine; valproic acid Hepatobiliary abnormality Cholelithiasis 6 Fenofibrate; gemfibrozil; nicotinic acid; sulindac; tacrine; tamoxifen Foetor hepaticus 7 Amiodarone; ciprofloxacin; methyldopa; omeprazole; ranitidine; terbinafine; valproic acid Hepatomegaly 5 Allopurinol; amiodarone; ciprofloxacin; cyclophosphamide; gentamicin S2 ALTEX 34(3), SUPPLEMENTARY DATA LIU ET AL. Categories Number of Compound names compounds Jaundice 49 Acarbose; acetazolamide; allopurinol; amitriptyline; captopril; carbamazepine; chlorpropamide; ciprofloxacin; cyclophosphamide; danazol; diazepam; diclofenac; disopyramide; doxorubicin; famotidine; fenofibrate; fluphenazine; flutamide; furosemide; gemfibrozil; glibenclamide; haloperidol; ibuprofen; imipramine; isoniazid; labetalol; mefenamic acid; methimazole; methyldopa; methyltestosterone; nicotinic acid; nifedipine; nitrofurantoin; omeprazole; pemoline; promethazine; propylthiouracil; quinidine; ranitidine; rifampicin; simvastatin; sulfasalazine; sulindac; terbinafine; thioridazine; ticlopidine; triamterene; triazolam; valproic acid Jaundice cholestatic 21 Acetazolamide; allopurinol; captopril; chlorpropamide; ciprofloxacin; danazol; disopyramide; doxorubicin; famotidine; fluphenazine; flutamide; furosemide; gemfibrozil; glibenclamide; labetalol; methyltestosterone; nitrofurantoin; ranitidine; simvastatin; sulfasalazine; ticlopidine Histologic findings Hyperbilirubinaemia 7 Allopurinol; ciprofloxacin; cyclophosphamide; doxorubicin; isoniazid; nicotinic acid; omeprazole Hepatitis 43 Acarbose; allopurinol; amiodarone; amitriptyline; captopril; carbamazepine; ciprofloxacin; clomipramine; dantrolene; diclofenac; disulfiram; doxorubicin; ethambutol; famotidine; fenofibrate; fluphenazine; flutamide; glibenclamide; ibuprofen; isoniazid; labetalol; mefenamic acid; metformin; methimazole; methyldopa; mexiletine; nicotinic acid; nifedipine; nitrofurantoin; omeprazole; papaverine; pemoline; phenytoin; propylthiouracil; quinidine; ranitidine; rifampicin; simvastatin; sulfasalazine; sulindac; tamoxifen; ticlopidine; valproic acid Hepatic cirrhosis 7 Amiodarone; diclofenac; fenofibrate; papaverine; simvastatin; sulfasalazine; valproic acid Liver disorder 8 Amiodarone; ciprofloxacin; glibenclamide; methyldopa; omeprazole; ranitidine; terbinafine; valproic acid Hepatic function abnormal 33 Acarbose; acetazolamide; amiodarone; azathioprine; carbamazepine; carboplatin; ciprofloxacin; clomipramine; cyclophosphamide; danazol; diclofenac; fenofibrate; fluphenazine; gemfibrozil; glibenclamide; haloperidol; ibuprofen; isoniazid; ketoconazole; methyldopa; mexiletine; nicotinic acid; omeprazole; pemoline; phenytoin; quinidine; rifampicin; simvastatin; sulfasalazine; sulindac; tamoxifen; terbinafine; ticlopidine Steatosis 13 Amitriptyline; colchicine; coumarin; diltiazem; disulfiram; ethanol; ethinylestradiol; hydroxyzine; imipramine; lomustine; methapyrilene; tetracycline; vitamin A Hepatic necrosis 13 Acetazolamide; allopurinol; ciprofloxacin; diclofenac; flutamide; ibuprofen; labetalol; mexiletine; nitrofurantoin; omeprazole; simvastatin; sulfasalazine; ticlopidine Cytolytic hepatitis 10 Acarbose; azathioprine; captopril; ciprofloxacin; colchicine; fluphenazine; isoniazid; phenobarbital; phenytoin; sulfasalazine ALTEX 34(3), SUPPLEMENTARY DATA S3 LIU ET AL. Tab. S3: Compound information Names Name Abbr. CAS No. Pub CID SMILES code (From PubChem) acarbose ACA 56180-94-0 441184 C[C@@H]1[C@H]([C@@H]([C@H]([C@H](O1)O[C@@H]2[C@H] (O[C@@H]([C@@H]([C@H]2O)O)O[C@@H]3[C@H](O[C@H] ([C@@H]([C@H]3O)O)O)CO)CO)O)O)N[C@H]4C=C([C@@H] ([C@@H]([C@H]4O)O)O)CO acetamidofluorene AAF 9006-42-2 5897 CC(=O)NC1=CC2=C(C=C1)C3=CC=CC=C3C2 acetaminophen APAP 103-90-2 1983 CC(=O)NC1=CC=C(C=C1)O acetazolamide ACZ 59-66-5 1986 CC(=O)NC1=NN=C(S1)S(=O)(=O)N ajmaline AJM 12/7/4360 20367 CCC1[C@H](N2C3CC1C4C2CC5([C@H]3N(C6=CC=CC=C65)C) [C@@H]4O)O allopurinol APL 315-30-0 2094 C1=C2C(=NC=NC2=O)NN1 allyl alcohol AA 107-18-6 7858 C=CCO amiodarone AM 1951-25-3 2157 CCCCC1=C(C2=CC=CC=C2O1)C(=O)C3=CC(=C(C(=C3)I)OCCN (CC)CC)I amitriptyline AMT 50-48-6 2160 CN(C)CCC=C1C2=CC=CC=C2CCC3=CC=CC=C31 aspirin ASA 50-78-2 2244 CC(=O)OC1=CC=CC=C1C(=O)O azathioprine AZP 446-86-6 2265 CN1C=NC(=C1SC2=NC=NC3=C2NC=N3)[N+](=O)[O-] bendazac BDZ 20187-55-7 2313 C1=CC=C(C=C1)CN2C3=CC=CC=C3C(=N2)OCC(=O)O benzbromarone BBr 3562-84-3 2333 CCC1=C(C2=CC=CC=C2O1)C(=O)C3=CC(=C(C(=C3)Br)O)Br benziodarone BZD 68-90-6 6237 CCC1=C(C2=CC=CC=C2O1)C(=O)C3=CC(=C(C(=C3)I)O)I bromobenzene BBZ 108-86-1 7961 C1=CC=C(C=C1)Br bromoethylamine BEA 107-09-5 7851 C(CBr)N bucetin BCT 1083-57-4 14130 CCOC1=CC=C(C=C1)NC(=O)CC(C)O caffeine