RESUMEN

Drug-induced liver toxicity is one of the significant safety challenges for the patient's health and the pharmaceutical industry. It causes termination of drug candidates in clinical trials and also the retractions of approved drugs from the market. Thus, it is essential to identify hepatotoxic compounds in the initial stages of drug development process. The purpose of this study is to construct quantitative structure activity relationship models using machine learning algorithms and systematical feature selection methods for molecular descriptor sets. The models were built from a large and diverse set of 1253 drug compounds and were validated internally with 10-fold cross-validation. In this study, we applied a variety of feature selection techniques to extract the optimal subset of descriptors as modeling features to improve the prediction performance. Experimental results suggested that the support vector machine-based classifier had achieved a better classification accuracy with reduced molecular descriptors. The final optimal model provides an accuracy of 0.811, a sensitivity of 0.840, a specificity of 0.783 and Mathew's correlation coefficient of 0.623 with an internal validation set. Furthermore, this model outperformed the prior studies while evaluated in both the internal and external test sets. The utilization of distinct optimal molecular descriptors as modeling features produce an in silico model with a superior performance.

Asunto(s)

Enfermedad Hepática Inducida por Sustancias y Drogas , Simulación por Computador , Hígado/efectos de los fármacos , Modelos Biológicos , Relación Estructura-Actividad Cuantitativa , Máquina de Vectores de Soporte , Exactitud de los Datos , Humanos , Sensibilidad y Especificidad

RESUMEN

Introduction:Safety and tolerability is a critical area where improvements are needed to decrease the attrition rates during development of new drug candidates. Modeling approaches, when smartly implemented, can contribute to this aim.Areas covered:The focus of this review was on modeling approaches applied to four kinds of drug-induced toxicities: hematological, immunological, cardiovascular (CV) and liver toxicity. Papers, mainly published in the last 10 years, reporting models in three main methodological categories - computational models (e.g., quantitative structure-property relationships, machine learning approaches, neural networks, etc.), pharmacokinetic-pharmacodynamic (PK-PD) models, and quantitative system pharmacology (QSP) models - have been considered.Expert opinion:The picture observed in the four examined toxicity areas appears heterogeneous. Computational models are typically used in all areas as screening tools in the early stages of development for hematological, cardiovascular and liver toxicity, with accuracies in the range of 70-90%. A limited number of computational models, based on the analysis of drug protein sequence, was instead proposed for immunotoxicity. In the later stages of development, toxicities are quantitatively predicted with reasonably good accuracy using either semi-mechanistic PK-PD models (hematological and cardiovascular toxicity), or fully exploited QSP models (immuno-toxicity and liver toxicity).

Asunto(s)

Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Modelos Biológicos , Descubrimiento de Drogas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Humanos , Hígado , Aprendizaje Automático

RESUMEN

Background: Fluconazole-associated liver injury is estimated to occur in <10% of patients; however, effect of weight-based fluconazole dosing on liver injury is unknown. Furthermore, no studies have systematically applied the Drug-Induced Liver Injury Network (DILIN) Criteria to identify patients who may have drug-induced liver injury in an intensive care unit (ICU) setting. Objective: This study evaluated how often patients met DILIN criteria when receiving fluconazole daily doses of <6 mg/kg versus ⩾6 mg/kg. Methods: This dual-center, retrospective cohort study was performed in hospitalized critically ill fluconazole recipients. We compared liver function tests (LFTs) upon fluconazole initiation to peak LFTs within 2 weeks after discontinuation using DILIN criteria. The primary objective was to evaluate the number of patients meeting DILIN criteria when receiving fluconazole daily doses of <6 mg/kg versus ⩾6 mg/kg. Secondary objectives were to evaluate incidence of patients meeting DILIN criteria in patients with renal dysfunction, cirrhosis, septic shock, or those receiving a loading dose. Results: Of 248 patients included, 90% had a documented fungal infection or received empiric therapy for suspected invasive candidiasis. In patients receiving <6 mg/kg of fluconazole, 55% (110/199) met DILIN criteria versus 46.9% (23/49) in the ⩾6 mg/kg cohort (P = .20). Only 14.5% of patients meeting DILIN criteria also met the definition for hepatocellular damage. Weight-based fluconazole dose and creatinine clearance <50 mL/min were not independent risk factors for meeting DILIN criteria. However, 77.3% of patients with cirrhosis met DILIN criteria (OR 4.84 [95% confidence interval, CI, 2.61-9.28]) and 76.3% with septic shock met DILIN criteria (OR 4.56 [95% CI, 2.44-8.88]). Conclusion: Weight-based fluconazole dosing did not affect the number of critically ill recipients who met DILIN criteria. However, DILIN criteria may overestimate the incidence of fluconazole-associated liver injury in critically ill patients.

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: The complexity of ingredients in traditional Chinese medical formulas and the limited consideration of toxicological responses are fundamental issues that hamper prognostic information of drug quality control. MATERIALS AND METHODS: A multidisciplinary approach for quality control of Qingkailing injection (QKL) regarding drug induced liver toxicity was described for the first time. High content image analysis (HCA) was combined with reverse-phase chromatographic separation and high-resolution MS detection technologies to provide the dynamic responses of drug induced HepG2 cell injury. Firstly, a simple and rapid method for simultaneous qualification and quantification of 21 major constituents in QKL was established and validated using ultra-high performance liquid chromatography-hybrid quadrupole-Orbitrap mass spectrometer (UHPLC-Q-Orbitrap), which were operated in full MS/dd-MS2 mode and thus simultaneously acquired quantitative high resolution (HR) full scan data and confirmatory HR MS2 data. Secondly, repeated semi-preparation HPLC was applied to obtain four fractions (F1-F4) for HCS analysis. Finally, potential hepatotoxicity was determined by five hepatotoxicity biomarkers, including cell loss, DNA condense, glutathione (GSH) depletion, reactive oxygen species (ROS) formation, and mitochondria membrane potential (MMP) depolarization. RESULTS: The detection in polarity switching mode empowered the coverage of comprehensive constituents with different chemical properties. Satisfactory linearity precisions, repeatability, stability, and recovery were achieved. QKL injection significantly induced HepG2 cell injury above the concentration of 1.25% (v/v). Meanwhile, flavone glycosides (F3) and stinasterols (F4) fractions exhibited hepatotoxicity above 75µg/mL and 50µg/mL, respectively. Still further, baicalin originated from F3 significantly caused cell loss and glutathione (GSH) depletion. In parallel, hyodeoxycholic acid from F4 induced cell loss, nucleus condense, and GSH reduction as well. CONCLUSIONS: Our work provides multiple perspectives based on injection-fractions-single compound format to improve QKL pharmacovigilance through revealing the potential hepatotoxic material basis. Additionally, our study provides an integrating paradigm for the comprehensive and systematic quality control of traditional Chinese medical formulas.

Asunto(s)

Ácido Desoxicólico/toxicidad , Medicamentos Herbarios Chinos/química , Flavonoides/toxicidad , Biomarcadores , Enfermedad Hepática Inducida por Sustancias y Drogas , Células Hep G2 , Humanos , Control de Calidad

RESUMEN

The incidence of inflammatory bowel diseases (IBD) is rising worldwide. The therapeutic options for IBD are expanding, and the number of drugs with new targets will rapidly increase in coming years. A rapid step-up approach with close monitoring of intestinal inflammation is extensively used. The fear of side effects represents one the most limiting factor of their use. Despite a widespread use for years, drug induced liver injury (DILI) management remains a challenging situation with Azathioprine and Methotrexate. DILI seems less frequent with anti-tumor necrosis factor agents and new biologic therapies. The aim of this review is to report incidence, physiopathology and practical guidelines in case of DILI occurrence with the armamentarium of old and new drugs in the field of IBD.

RESUMEN

Nefazodone, an antagonist for the 5-hydroxytryptanine receptor, has been used for the treatment of depression. Acute liver injury has been documented to be associated with the use of nefazodone; however, the mechanisms of nefazodone-induced liver toxicity are not well defined. In this report, using biochemical and molecular analyses, we characterized the molecular mechanisms underlying the hepatotoxicity of nefazodone. We found that nefazodone induced endoplasmic reticulum (ER) stress in HepG2 cells, as the expression of typical ER stress markers, including CHOP, ATF-4, and p-eIF2α, was significantly increased, and splicing of XBP1 was observed. Nefazodone-suppressed protein secretion was evaluated using a Gaussia luciferase reporter assay that measures ER stress. The ER stress inhibitors (4-phenylbutyrate and salubrinal) and knockdown of ATF-4 gene attenuated nefazodone-induced ER stress and cytotoxicity. Nefazodone activated the MAPK signaling pathway, as indicated by increased phosphorylation of JNK, ERK1/2, and p38. Inhibition of ERK1/2 reduced ER stress caused by nefazodone. Taken together, our findings suggest that ER stress contributes to nefazodone-induced toxicity in HepG2 cells and that the MAPK signaling pathway plays an important role in ER stress.

Asunto(s)

Antidepresivos de Segunda Generación/toxicidad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Triazoles/toxicidad , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Antidepresivos de Segunda Generación/metabolismo , Muerte Celular/efectos de los fármacos , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Relación Dosis-Respuesta a Droga , Activación Enzimática , Factor 2 Eucariótico de Iniciación/metabolismo , Células Hep G2 , Hepatocitos/enzimología , Hepatocitos/patología , Humanos , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/genética , Fosforilación , Piperazinas , Interferencia de ARN , Empalme del ARN , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Factor de Transcripción CHOP/metabolismo , Transfección , Triazoles/metabolismo , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismo

RESUMEN

The generation of reactive metabolites from therapeutic agents is one of the major mechanisms of drug-induced liver injury (DILI). In order to evaluate metabolism-related toxicity and improve drug efficacy and safety, we generated a battery of HepG2-derived cell lines that express 14 cytochrome P450s (CYPs) (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5 and 3A7) individually using a lentiviral expression system. The expression/production of a specific CYP in each cell line was confirmed by an increased abundance of the CYP at both mRNA and protein levels. Moreover, the enzymatic activities of representative CYPs in the corresponding cell lines were also measured. Using our CYP-expressed HepG2 cells, the toxicity of three drugs that could induce DILI (amiodarone, chlorpromazine and primaquine) was assessed, and all of them showed altered (increased or decreased) toxicity compared to the toxicity in drug-treated wild-type HepG2 cells. CYP-mediated drug toxicity examined in our cell system is consistent with previous reports, demonstrating the potential of these cells for assessing metabolism-related drug toxicity. This cell system provides a practical in vitro approach for drug metabolism screening and for early detection of drug toxicity. It is also a surrogate enzyme source for the enzymatic characterization of a particular CYP that contributes to drug-induced liver toxicity.

Asunto(s)

Amiodarona/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Hígado/efectos de los fármacos , Antimaláricos/toxicidad , Antipsicóticos/toxicidad , Línea Celular , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Clorpromazina/toxicidad , Inhibidores Enzimáticos del Citocromo P-450/toxicidad , Sistema Enzimático del Citocromo P-450/genética , Evaluación Preclínica de Medicamentos/métodos , Expresión Génica , Células Hep G2 , Humanos , Hígado/metabolismo , Hígado/patología , Primaquina/toxicidad , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/genética

RESUMEN

The risk of drug-induced liver injury (DILI) is of great concern to the pharmaceutical industry. It is well-known that metabolic activation of drugs to form toxic metabolites (TMs) is strongly associated with DILI onset. Drug-induced mitochondrial dysfunction is also strongly associated with increased risk of DILI. However, it is difficult to determine the target of TMs associated with exacerbation of DILI because of difficulties in identifying and purifying TMs. In this study, we propose a sequential in vitro assay system to assess TM formation and their ability to induce mitochondrial permeability transition (MPT) in a one-pot process. In this assay system, freshly-isolated rat liver mitochondria were incubated with reaction solutions of 44 test drugs preincubated with liver microsomes in the presence or absence of NADPH; then, NADPH-dependent MPT pore opening was assessed as mitochondrial swelling. In this assay system, several hepatotoxic drugs, including benzbromarone (BBR), significantly induced MPT in a NADPH-dependent manner. We investigated the rationality of using BBR as a model drug, since it showed the most prominent MPT in our assay system. Both the production of a candidate toxic metabolite of BBR (1',6-(OH)2 BBR) and NADPH-dependent MPT were inhibited by several cytochrome P450 (CYP) inhibitors (clotrimazole and SKF-525A, 100µM). In summary, this assay system can be used to evaluate comprehensive metabolite-dependent MPT without identification or purification of metabolites.

Asunto(s)

Benzbromarona/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Hígado/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias Hepáticas/efectos de los fármacos , Activación Metabólica , Animales , Benzbromarona/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Inhibidores del Citocromo P-450 CYP2C9/farmacología , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Cinética , Hígado/metabolismo , Hígado/patología , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Mitocondrias Hepáticas/metabolismo , Mitocondrias Hepáticas/patología , Dilatación Mitocondrial/efectos de los fármacos , NADP/metabolismo , Ratas Sprague-Dawley

RESUMEN

We herein report a case of fatal fulminant hepatitis secondary to crizotinib administration. The patient was 54-year-old female with a history of Hepatitis C infection (not current), dermatomyositis and steroid-induced diabetes mellitus. She was diagnosed with advanced lung adenocarcinoma with anaplastic lymphoma kinase rearrangement. We began 400 mg of crizotinib as first-line therapy. No adverse effects were seen until Day 16. On Day 29, she was admitted to hospital with elevated liver enzymes (aspartate aminotransferase 3236 IU/l, alanine aminotransferase 5201 IU/l) and coagulopathy (prothrombin time <10%), and was diagnosed with crizotinib-induced fulminant hepatitis. We started intensive care, using plasma exchange, continuous hemodiafiltration and high-dose steroid therapy. Unfortunately, she did not respond to therapies, and died on Day 36. The mechanism and risk factors of crizotinib-induced hepatotoxicity are uncertain. Physicians should be aware of possible adverse effects of crizotinib. A systemic survey is imperative to identify possible risk factors of crizotinib-related hepatotoxicity.

Asunto(s)

Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/efectos adversos , Piridinas/efectos adversos , Proteínas Tirosina Quinasas Receptoras/análisis , Alanina Transaminasa/sangre , Quinasa de Linfoma Anaplásico , Antineoplásicos/administración & dosificación , Aspartato Aminotransferasas/sangre , Carcinoma de Pulmón de Células no Pequeñas/química , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Enfermedad Hepática Inducida por Sustancias y Drogas/terapia , Crizotinib , Resultado Fatal , Femenino , Humanos , Neoplasias Pulmonares/química , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Factores de Riesgo

RESUMEN

Sertraline is used for the treatment of depression, and is also used for the treatment of panic, obsessive-compulsive, and post-traumatic stress disorders. Previously, we have demonstrated that sertraline caused hepatic cytotoxicity, with mitochondrial dysfunction and apoptosis being underlying mechanisms. In this study, we used microarray and other biochemical and molecular analyses to identify endoplasmic reticulum (ER) stress as a novel molecular mechanism. HepG2 cells were exposed to sertraline and subjected to whole genome gene expression microarray analysis. Pathway analysis revealed that ER stress is among the significantly affected biological changes. We confirmed the increased expression of ER stress makers by real-time PCR and Western blots. The expression of typical ER stress markers such as PERK, IRE1α, and CHOP was significantly increased. To study better ER stress-mediated drug-induced liver toxicity; we established in vitro systems for monitoring ER stress quantitatively and efficiently, using Gaussia luciferase (Gluc) and secreted alkaline phosphatase (SEAP) as ER stress reporters. These in vitro systems were validated using well-known ER stress inducers. In these two reporter assays, sertraline inhibited the secretion of Gluc and SEAP. Moreover, we demonstrated that sertraline-induced apoptosis was coupled to ER stress and that the apoptotic effect was attenuated by 4-phenylbutyrate, a potent ER stress inhibitor. In addition, we showed that the MAP4K4-JNK signaling pathway contributed to the process of sertraline-induced ER stress. In summary, we demonstrated that ER stress is a mechanism of sertraline-induced liver toxicity.

Asunto(s)

Estrés del Retículo Endoplásmico/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sertralina/farmacología , Fosfatasa Alcalina/metabolismo , Apoptosis/efectos de los fármacos , Biomarcadores , Western Blotting , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular , Expresión Génica/efectos de los fármacos , Vectores Genéticos , Humanos , Análisis por Micromatrices , Reacción en Cadena de la Polimerasa , Empalme del ARN/efectos de los fármacos , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa

RESUMEN

AIM: Unlike other dipeptidyl peptidase 4 (DPP-4) inhibitors, the excretion of linagliptin is mainly through a biliary route. Despite this fact, liver injury with linagliptin has thus far not been reported in the literature. However, this report describes the first case of probable linagliptin-induced liver toxicity. METHODS: The clinical history, diagnosis, investigations and drug treatment of the patient are reviewed here. RESULTS: A 58-year-old Japanese woman presented with fatigue, nausea, jaundice and marked elevations of hepatic enzymes 4weeks after starting linagliptin 5mg/day as monotherapy. No other medications were taken, and imaging studies revealed no other obvious causes of hepatic injury. Tests for viral serology and antinuclear antigen were negative. Symptoms disappeared and the levels of hepatic parameters (serum aminotransferases and biliary enzymes) slowly recovered after discontinuation of linagliptin. The slow recovery process may have been due to the very long half-life of the drug. The patient's Naranjo scale score was 6 and RUCAM score was 7. CONCLUSION: Although linagliptin currently carries no liver warnings, it may be necessary to monitor hepatic function in some patients upon administration of this drug until further evidence is obtained.

Asunto(s)

Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Purinas/efectos adversos , Quinazolinas/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/complicaciones , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Relación Dosis-Respuesta a Droga , Fatiga/etiología , Femenino , Semivida , Humanos , Ictericia/etiología , Linagliptina , Tasa de Depuración Metabólica , Persona de Mediana Edad , Náusea/etiología , Purinas/administración & dosificación , Quinazolinas/administración & dosificación

RESUMEN

Liver injury resulting from exposure to drugs and chemicals is a major health problem. Autophagy is an important factor in a wide range of diseases, such as cancer, liver disease, muscular disorder, neurodegeneration, pathogen infection, and aging, and emerging evidence indicates that autophagy makes a substantial contribution to the pathogenesis of drug- and chemical-induced liver toxicity. In this review, we summarize current knowledge on autophagy triggered by toxicants/toxins, the protective role of autophagy in liver toxicity, and the underlying molecular mechanisms. We also highlight experimental approaches for studying autophagy.

RESUMEN

Amiodarone is a benzofuran class III antiarrhythmic drug used to treat a wide spectrum of ventricular tachyarrhythmias. The parenteral formulation is prepared in polysorbate 80 diluent. We report an unusual case of acute elevation of aminotransaminase concentrations after the initiation of intravenous amiodarone. An 88-year-old Caucasian female developed acute hepatitis and renal failure after initiating intravenous amiodarone for atrial fibrillation with a rapid ventricular response in the setting of acutely decompensated heart failure and hepatic congestion. Liver transaminases returned to baseline within 7 days after discontinuing the drug. Researchers hypothesized that this type of injury is related to liver ischemia with possible superimposed direct drug toxicity. The CIOMS/RUCAM scale identifies our patient's acute hepatitis as a highly probable adverse drug reaction. Future research is needed to understand the mechanisms by which hyperacute drug toxicity occurs in the setting of impaired hepatic perfusion and venous congestion.