Table 2.
Characteristics of 26 test compounds
| DILI Concern Score | Transporter Inhibition | Mol Wt | PSA, Å2 | LogD (pH 7.4) | WHO Essential Medicines | FDA Model Substrates or Inhibitors | Reference | |
|---|---|---|---|---|---|---|---|---|
| Exogenous compounds | ||||||||
| Amoxicillin | 2, cholestatic DILI | Not reported | 365.4 | 158 | −3.02 | X | 12 | |
| Azithromycin | 2, cholestatic DILI | Not reported | 748.98 | 180 | 1.36 | X | 12 | |
| Ciprofloxacin | 1, cholestatic DILI | Not reported | 331.34 | 72.9 | −2.23 | X | 12 | |
| Clavulanic acid | 2, cholestatic DILI (combination with amoxicillin) | Not reported | 199.16 | 87.1 | −4.72 | X | 16 | |
| Digoxin | 4 | OSTα/β inhibitor | 780.94 | 203 | 1.26 | X | x | 54, 59 |
| Dronedarone | 1 | BSEP, MRP3 inhibitor | 556.76 | 97.2 | 3.98 | x | 3, 12, 45 | |
| Fidaxomicin | 4 | MRP3 inhibitor | 1058 | 267 | 6.59 | 3 | ||
| Indomethacin | 1 | OSTα/β, ASBT, BSEP, MRP3, MRP4 inhibitor | 357.79 | 68.5 | 0.75 | 36, 45, 54, 59, 64 | ||
| Levofloxacin | 1, cholestatic DILI | Not reported | 361.37 | 73.3 | −2.08 | 6 | ||
| MK571 | 4, not in clinical use | BSEP, MRP2, MRP3, MRP4 inhibitor | 515.09 | 121 | 2.35 | 3, 45 | ||
| Paroxetine | 2 | Pgp inhibitor | 329.37 | 39.7 | 3.89 | 12 | ||
| Probenecid | 3 | OSTα/β, BSEP, MRP3, MRP4 inhibitor | 285.36 | 83.1 | 0.01 | x | 15, 36, 54, 59 | |
| Rosuvastatin | 2 | BCRP inhibitor | 481.54 | 149 | −1.77 | x | 6 | |
| Simvastatin | 2 | ASBT, BSEP inhibitor | 418.57 | 72.8 | 4.6 | X | x | 45, 64 |
| Spironolactone | 2 | OSTα/β, ASBT inhibitor | 416.57 | 85.7 | 2.78 | X | 54, 64 | |
| Sulfobromophthalein | 4 | OSTα/β inhibitor | 794 | 192.25 | −2.48 | 54 | ||
| Sulfamethoxazole | 2 (combination with trimethoprim) | Not reported | 253.28 | 107 | −0.56 | X | 6 | |
| Suramin | 4 | MRP3 inhibitor | 1297.3 | 534 | −12.23 | X | 3, 6 | |
| Toremifene | 3 | Not reported | 405.96 | 12.5 | 5.56 | 12 | ||
| Trimethoprim | 2, cholestatic DILI | MRP3, MRP4 inhibitor | 290.32 | 106 | −1.15 | X | x | 36 |
| Troglitazone | 1 | BSEP, MRP2, MRP3, MRP4 inhibitor | 441.54 | 110 | 3.26 | 15, 45 | ||
| Troglitazone sulfate* | 3 | BSEP inhibitor, MRP4 | 521.6 | 162 | −0.19 | 25, 62 | ||
| Valproic acid | 1, cholestatic DILI | Not reported | 144.21 | 37.3 | 0.1 | X | 12 | |
| Endogenous compounds | ||||||||
| Estrone sulfate | 3 | OSTα/β inhibitor | 350.4 | 89.05 | −1.05 | x | 54, 59 | |
| Glycochenodeoxycholic acid (GCDCA) | Not reported | 471.62 | 106.86 | −0.51 | 28 | |||
| Taurolithocholic acid sulfate (TLCAS) | OSTα/β inhibitor | 586.76 | 167 | −2.33 | 54, 59 | |||
Information includes score for drug-induced liver injury (DILI) concerns (1 = most, 2 = less, 3 = ambiguous, 4 = none), transporter inhibition, physicochemical properties, inclusion in the World Health Organization (WHO) model list of essential medicines (indicated by X), and listing as a US Food and Drug Administration (FDA) model substrate or inhibitor for transporters (indicated by x). ASBT, apical sodium-dependent bile salt transporter; BCRP, breast cancer resistance protein; BSEP, bile salt export pump; LogD, distribution constant; MRP, multidrug resistance-associated protein; OSTα/β, organic solute transporter α/β; Pgp, P-glycoprotein; PSA, polar surface area. Physicochemical properties, PSA, and LogD of the compounds were obtained from SciFinder, Chemical Abstracts Service (American Chemical Society, Columbus, OH), and ChemSpider (Royal Society of Chemistry, Raleigh, NC) (May 8, 2017).
Main metabolite of troglitazone.