Association Between the Characteristics of Small-molecule Kinase Inhibitors and Drug-induced Liver Injury: A Scoping Study (Preprint)

BACKGROUND Preventing Drug-induced liver injury (DILI) in advance is an important task to improve drug safety and protect patient health. It was reported that more than half of small-molecule kinase inhibitors (KIs) induced DILI clinically. Meanwhile, numerous studies have shown a close relationship between mitochondrial damage and the generation of DILI. OBJECTIVE We aimed to focused on KIs to find factors related to DILI occurrence and study the binding potential between the whole class of drugs and mitochondrial proteins and further analysis of the key proteins in silico. METHODS 1,223 drugs approved by the Food and Drug Administration (FDA) were collected and analyzed, including 44 KIs. Fisher exact test was used to analyze DILI potential and risk of different factors. 187 human mitochondrial proteins were further collected and high-throughput molecular docking was performed between them and drugs in the data set. RESULTS Be The possibility of KIs to produce DILI is much higher than other types (odds ratio [OR] = 46.89, 95% CI [confidence interval] = 6.44 ~ 341.63, P = 9.28E-13). A few DILI risk factors were found, including molecular weight (MW) between 400 and 600, the defined daily dose (DDD) greater than or equal to 100mg/day, the octanol-water partition coefficient (LogP) greater than or equal to 3, and the degree of liver metabolism (LM) more than 50% (‘400 ≤ MW < 600 & LogP ≥ 3 & DDD ≥ 100 & LM ≥ 50%’). Drugs that met this combination of rules were found to have higher DILI risk than controls (OR = 8.28, 95% CI = 2.46 ~ 27.82, P = 4.82E-05, PPV [positive predictive value] = 88%) and were more likely to cause severe DILI (OR = 8.26, 95% CI = 2.25 ~ 30.26, P = 5.06E-04). The docking results showed that KIs had significant higher affinity with human mitochondrial proteins (P = 4.19E-11), which may be an implication for higher DILI potential. CONCLUSIONS KIs were found to have the highest odds ratio of causing DILI. Some characteristics of KIs were significantly related to the production of DILI. And the average docking scores of KIs drugs were found to be significant different from other classes. Further analysis identified the top binding mitochondrial proteins for KIs, which may help with the study of the mechanism of DILI. CLINICALTRIAL Not applicable.

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BML-257, a small molecule that protects against drug induced liver injury in zebrafish

10.1101/2022.01.09.475146 ◽

2022 ◽

Author(s):

Urmila Jagtap ◽

Sandeep Basu ◽

Lavanya Lokhande ◽

Nikhil Bharti ◽

Chetana Sachidanandan

Keyword(s):

Liver Injury ◽

Small Molecule ◽

Liver Damage ◽

Protective Action ◽

Damage Model ◽

Akt Inhibitor ◽

Drug Induced ◽

Specific Expression ◽

Drug Induced Liver Injury ◽

Chemical Screen

The use of many essential drugs is restricted due to their deleterious effects on the liver. Molecules that can prevent or protect the liver from drug induced liver injury (DILI) would be valuable in such situations. We used hepatocyte-specific expression of bacterial nitroreductase in zebrafish to cause temporally controlled liver damage. This transgenic line was used to run a whole organism based chemical screen in zebrafish larvae. In this screen we identified BML-257, a potent small molecule AKT inhibitor, that protected the liver against metronidazole-induced liver injury. BML-257 also showed potent prophylactic and pro-regenerative activity in this liver damage model. BML-257 also showed remarkable protective action in two independent toxicological models of liver injury caused by acetaminophen and Isoniazid. This suggests that BML-257 may have the potential to protect against multiple kinds of drug induced liver injury.

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Predictive Model for Drug-Induced Liver Injury Using Deep Neural Networks Based on Substructure Space

Molecules ◽

10.3390/molecules26247548 ◽

2021 ◽

Vol 26 (24) ◽

pp. 7548

Author(s):

Myung-Gyun Kang ◽

Nam Sook Kang

Keyword(s):

Liver Injury ◽

Predictive Model ◽

Computational Models ◽

Applicability Domain ◽

Drug Induced ◽

Validation Data ◽

Data Set ◽

Adequate Model ◽

Drug Induced Liver Injury ◽

External Data

Drug-induced liver injury (DILI) is a major concern for drug developers, regulators, and clinicians. However, there is no adequate model system to assess drug-associated DILI risk in humans. In the big data era, computational models are expected to play a revolutionary role in this field. This study aimed to develop a deep neural network (DNN)-based model using extended connectivity fingerprints of diameter 4 (ECFP4) to predict DILI risk. Each data set for the predictive model was retrieved and curated from DILIrank, LiverTox, and other literature. The best model was constructed through ten iterations of stratified 10-fold cross-validation, and the applicability domain was defined based on integer ECFP4 bits of the training set which represented substructures. For the robustness test, we employed the concept of the endurance level. The best model showed an accuracy of 0.731, a sensitivity of 0.714, and a specificity of 0.750 on the validation data set in the complete applicability domain. The model was further evaluated with four external data sets and attained an accuracy of 0.867 on 15 drugs with DILI cases reported since 2019. Overall, the results suggested that the ECFP4-based DNN model represents a new tool to identify DILI risk for the evaluation of drug safety.

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NAT2 slow acetylator is associated with anti-tuberculosis drug-induced liver injury severity in indonesian population

Pharmacogenomics ◽

10.2217/pgs-2019-0131 ◽

2019 ◽

Vol 20 (18) ◽

pp. 1303-1311

Author(s):

Rika Yuliwulandari ◽

Kinasih Prayuni ◽

Retno Wilujeng Susilowati ◽

Abdul Salam M Sofro ◽

Katsushi Tokunaga ◽

...

Keyword(s):

Liver Injury ◽

Odds Ratio ◽

Injury Severity ◽

Severe Disease ◽

Drug Induced ◽

Slow Acetylator ◽

Direct Dna Sequencing ◽

Drug Induced Liver Injury ◽

Indonesian Population ◽

Acetylator Status

Aim: We investigated the contribution of NAT2 variants and acetylator status to anti-tuberculosis drug-induced liver injury (AT-DILI) severity. Materials & methods: 100 patients with clinically severe AT-DILI and 210 non-AT-DILI controls were subjected to NAT2 genotyping by direct DNA sequencing. Results: NAT2 slow acetylator was significantly associated with AT-DILI risk (p = 2.7 × 10-7; odds ratio [95% CI] = 3.64 [2.21–6.00]). Subgroup analysis of NAT2 ultra-slow acetylator revealed a stronger association with AT-DILI risk (p = 4.3 × 10-6; odds ratio [95% CI] = 3.37 [2.00–5.68]). Subset analysis of NAT2 acetylator status and severity grade confirmed these results in AT-DILI patients with more severe disease whereas fast and intermediate acetylator phenotypes were associated with a decreased AT-DILI risk. Conclusion: We elucidated the role of NAT2 phenotypes in AT-DILI in Indonesian population, suggesting that NAT2 genotype and phenotype determination are important to reduce AT-DILI risk.

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Leberschaden unter oraler Antikoagulation, Statin- und ACE-Hemmertherapie

Praxis ◽

10.1024/1661-8157/a000298 ◽

2010 ◽

Vol 99 (21) ◽

pp. 1259-1265 ◽

Cited By ~ 2

Author(s):

Bruggisser ◽

Terraciano ◽

Rätz Bravo ◽

Haschke

Keyword(s):

Liver Injury ◽

Wird Eine ◽

Drug Induced ◽

Drug Induced Liver Injury

Ein 71-jähriger Patient stellt sich mit Epistaxis und ikterischen Skleren auf der Notfallstation vor. Der Patient steht unter einer Therapie mit Phenprocoumon, Atorvastatin und Perindopril. Anamnestisch besteht ein langjähriger Alkoholabusus. Laborchemisch werden massiv erhöhte Leberwerte (ALAT, Bilirubin) gesehen. Der INR ist unter oraler Antikoagulation und bei akuter Leberinsuffizienz >12. Die weiterführenden Abklärungen schliessen eine Virushepatitis und eine Autoimmunhepatitis aus. Nachdem eine Leberbiopsie durchgeführt werden kann, wird eine medikamentös-toxische Hepatitis, ausgelöst durch die Komedikation von Atorvastatin, Phenprocoumon und Perindopril bei durch Alkohol bereits vorgeschädigter Leber diagnostiziert. Epidemiologie, Pathophysiologie und Klink der medikamentös induzierten Leberschäden (drug induced liver injury, DILI), speziell von Coumarinen, Statinen und ACE-Hemmern werden im Anschluss an den Fallbericht diskutiert.

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