Shah, Falgun published the artcileSetting clinical exposure levels of concern for drug-induced liver injury (DILI) using mechanistic in vitro assays, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is drug induced liver injury assay hepatotoxicity BSEP mitochondria inhibition; Liver Toxicity Knowledge Base; drug-induced liver injury; plasma exposure; safety margin.
Severe drug-induced liver injury (DILI) remains a major safety issue due to its frequency of occurrence, idiosyncratic nature, poor prognosis, and diverse underlying mechanisms. Numerous exptl. approaches have been published to improve human DILI prediction with modest success. A retrospective anal. of 125 drugs (70 = most-DILI, 55 = no-DILI) from the Food and Drug Administration Liver Toxicity Knowledge Base was used to investigate DILI prediction based on consideration of human exposure alone or in combination with mechanistic assays of hepatotoxic liabilities (cytotoxicity, bile salt export pump inhibition, or mitochondrial inhibition/uncoupling). Using this dataset, human plasma Cmax,total ≥ 1.1 μM alone distinguished most-DILI from no-DILI compounds with high sensitivity/specificity (80/73%). Accounting for human exposure improved the sensitivity/specificity for each assay and helped to derive predictive safety margins. Compounds with plasma Cmax,total ≥ 1.1 μM and triple liabilities had significantly higher odds ratio for DILI than those with single/dual liabilities. Using this approach, a subset of recent pharmaceuticals with evidence of liver injury during clin. development was recognized as potential hepatotoxicants. In summary, plasma Cmax,total ≥ 1.1 μM along with multiple mechanistic liabilities is a major driver for predictions of human DILI potential. In applying this approach during drug development the challenge will be generating accurate estimates of plasma Cmax, total at efficacious doses in advance of generating true exposure data from clin. studies. In the meantime, drug candidates with multiple hepatotoxic liabilities should be deprioritized, since they have the highest likelihood of causing DILI in case their efficacious plasma Cmax,total in humans is higher than anticipated.
Toxicological Sciences published new progress about Drug discovery. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.
Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem