clozapine and Chemical-and-Drug-Induced-Liver-Injury

Topics: Acetylcysteine; Chemical and Drug Induced Liver Injury; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Liver Failure, Acute; Middle Aged

To identify the clinical determinants of fever in clozapine users and their impact on management of clozapine treatment.. Articles published in English or French identified with a MEDLINE, Web of Sciences, Cochrane Library and PsycINFO search, from inception through February 2019, using the term "clozapine" in combination with "fever" OR "hyperthermia" OR "body temperature" OR "pyrexia" OR "febrile" OR "heat" OR "thermoregulation". Information extracted for each medical condition were frequency, time to onset after initiation of clozapine treatment, characteristics of fever, associated symptoms, laboratory tests used for diagnosis, course, lethality, discontinuation of clozapine. Data were synthesized narratively.. Our search yielded 394 unique hits published from 1993 to 2018. We included 73 articles in the review: two meta-analyses, 14 reviews, six epidemiological studies, 11 clinical studies and 40 case reports. During clozapine initiation, fever is most frequently benign and transient but should be closely monitored as it may be the first stage of potentially life-threatening adverse drug reactions (ADR) (agranulocytosis, neuroleptic malignant syndrome myocarditis, hepatitis, pancreatitis, nephritis, colitis, etc.). Other ADR associated with fever are independent of duration of exposure to clozapine (heat stroke, pneumonia, pulmonary embolism, necrotizing colitis). If fever is due to intercurrent infection, therapeutic drug monitoring is recommended to adjust clozapine daily dosage.. Benign causes of fever are much more frequent than life-threatening ADR during clozapine treatment. Discontinuation should not be considered as automatic in the event of fever, especially during the early phase of clozapine initiation.

Topics: Agranulocytosis; Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Colitis; Dose-Response Relationship, Drug; Drug Monitoring; Fever; Hepatitis; Humans; Infections; Lupus Erythematosus, Systemic; Myocarditis; Nephritis; Neuroleptic Malignant Syndrome; Pancreatitis; Pneumonia; Pulmonary Embolism; Schizophrenia; Serositis

Clozapine is the criterion standard in treatment-resistant schizophrenia. We sought to review data on several inflammatory effects associated with clozapine, specifically interstitial nephritis, hepatitis, and pancreatitis.. We conducted a systematic review to identify studies, published up until December 2017, describing clozapine-induced hepatitis, nephritis, and pancreatitis. The primary objective was to characterize the clinical characteristics associated with each of the specific inflammatory reactions to clozapine.. We identified 42 cases of inflammatory reactions associated with clozapine treatment- 20 :cases of clozapine-induced hepatitis, 11 cases of nephritis, and 11 of pancreatitis. The mean (SD) age was 38.8 (11.9) years. The mean (SD) dose of clozapine used was 252.4 (133.7) mg. Time to onset of pancreatitis (17.9 [11.2] days; range 4-35 days) was shorter than that for hepatitis (34.2 [20.1] days; range, 12-90 days) and nephritis (27.9 [27.0]; range, 8-90 days) but was not statistically significant (F = 2.267, P = 0.117). The mean (SD) time to recovery was shorter for cases of pancreatitis (15.7 [18.4] days) compared with cases of hepatitis (25.9 [16.5] days) and nephritis (24.5 [18.9] days). Three cases with hepatitis died. Seven of the cases had a clozapine rechallenge (hepatitis [n = 3], nephritis [n = 1], pancreatitis [n = 3]), with 5 having a recurrence at a mean (SD) onset of 3.5 (2.5) days (range, 1-7 days); 2 hepatitis cases were successfully rechallenged.. Clozapine-induced hepatitis, nephritis, and pancreatitis are uncommon adverse events, reflected in the paucity of case studies in the literature. Early recognition of the signs and symptoms of clozapine-associated hepatitis, nephritis, and pancreatitis is important, as when identified, clozapine should be urgently discontinued. Clozapine is associated with evidence of benign inflammatory processes; the extent to which hepatitis, and other inflammatory reactions, may be on a continuum with these more benign and self-limiting reactions is unclear, and this can only be resolved by prospectively following cohorts of clozapine-treated patients.

Topics: Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Humans; Nephritis, Interstitial; Observational Studies as Topic; Pancreatitis; Treatment Outcome

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Drug Labeling; Humans; Pharmaceutical Preparations; Risk

Atypical antipsychotics commonly cause isolated asymptomatic increase in the aminotransferase levels. Furthermore, the strategy in the choice of antipsychotic agent must take into account hepatic tolerance because of the non-negligible incidence of liver disorders among the psychiatric population. The aim of this article is to better understand the strategy to adopt during an increase of liver enzymes in a psychotic patient under atypical neuroleptic treatment.. A clinical case is presented of a female patient treated for psychotic decompensation with increase of liver enzymes (Olanzapine). Her treatment was changed several times over a period of 7 years and laboratory investigations were conducted simultaneously.. It seems that the increase of liver enzymes is slightly more frequent with Clozapine and Olanzapine than Risperidone, Perazine and Haloperiol.. The different mechanisms of hepatotoxicity are unknown at present but it seems that the hypersensibility mechanism is likely to be dose dependent. During an increase of enzymes, it is important to combine a control of hepatic enzymes with a reduction of neuroleptic dosage. Discontinuation should be considered if a continued increase of enzymes above certain values is shown or if a clinical symptom appears. We note also that some risk factors were found, including geriatric or pedopsychiatric age, obesity, and association with active ingredients or addictive substances responsible for hepatic disorders.

Topics: Age Factors; Antipsychotic Agents; Benzodiazepines; Chemical and Drug Induced Liver Injury; Clozapine; Dose-Response Relationship, Drug; Female; Haloperidol; Humans; Liver; Middle Aged; Olanzapine; Perazine; Risk Factors; Risperidone; Transaminases

Topics: Adult; Chemical and Drug Induced Liver Injury; Clozapine; Disease Management; Female; Humans; Middle Aged

Since its introduction to the United States in 1990, the benefits of clozapine use have been repeatedly validated. Clozapine remains the only antipsychotic with proven efficacy in treatment-resistant schizophrenia. Because clozapine has been part of the psychiatric pharmacopeia for considerably less time than neuroleptics, which have dominated the field for over 4 decades, its underutilization may be partly attributed to a lack of experience in managing associated side effects. Most side effects associated with clozapine are typical of antipsychotics in general, and with clozapine, these side effects are typically benign, tolerable, and manageable. It is conceivable that there remains a concern over the risk of agranulocytosis. However, the mandatory blood monitoring carried out through the Clozaril National Registry has considerably reduced the incidence of fully developed cases of agranulocytosis from premarketing values of approximately 1% to 2% to current values of 0.38% and virtually prevented mortalities. These values are likely to decrease further with the application of cytokine augmentation therapy among patients developing blood dyscrasias. Many side effects of clozapine are observed early after treatment onset and are greatly reduced by dose adjustments. Appropriate management of side effects will facilitate a maximization of the benefits of clozapine treatment. Clearly, the benefits of clozapine therapy far outweigh its risks.

Topics: Agranulocytosis; Antipsychotic Agents; Basal Ganglia Diseases; Chemical and Drug Induced Liver Injury; Clozapine; Drug Administration Schedule; Drug Monitoring; Humans; Incidence; Risk Factors; Schizophrenia; Sleep Wake Disorders; Tachycardia; Urinary Incontinence; Weight Gain

Two hundred thirty-eight patients treated with either haloperidol or clozapine were investigated to shed more light on the incidence and severity of antipsychotic-induced liver enzyme increase. Serum glutamic-pyruvic transaminase (SGPT) increase was most frequently seen in both treatment groups. When analyzing the incidence rates for patients with increased liver enzyme values (serum glutamic-oxaloacetic transaminase, SGPT, gamma-glutamyl transpeptidase) that were higher than twice the upper limit of the normal range, clozapine-treated patients showed an SGPT increase (37.3%) significantly more frequently than patients treated with haloperidol (16.6%). Both patients with higher clozapine plasma levels and male patients were at a higher risk for an SGPT increase. At least 60% of the increase of the different enzymes remitted within the first 13 weeks of treatment. In general, the authors conclude that clozapine-induced liver enzyme elevation seems to be a common and mostly transient phenomenon.

Topics: Adult; Alanine Transaminase; Antipsychotic Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clozapine; Enzymes; Female; Haloperidol; Humans; Liver Function Tests; Male; Prospective Studies; Sex Characteristics

Drug-induced liver injury (DILI) has been associated with various antipsychotic drugs (APDs). Comparative studies between individual APDs are largely not available.. Antipsychotic drug utilisation data and reports of severe antipsychotic DILI were assessed by using data from an observational pharmacovigilance programme-Arzneimittelsicherheit in der Psychiatrie (AMSP)-during the period 1993-2016.. Of the 333,175 patients treated with APDs, a total of 246 (0.07%) events of severe DILI were identified. Phenothiazines were associated with significantly higher rates of severe DILI (0.03%, 95% CI = 0.02-0.04) than thioxanthenes (0.01%, 95% CI = 0.00-0.02) or butyrophenones (0.01%, 95% CI = 0.00-0.01). Among individual drugs, olanzapine (0.12%, 95% CI = 0.10-0.16), perazine (0.09%, 95% CI = 0.05-0.15) and clozapine (0.09%, 95% CI = 0.10-0.12 ranked highest. In 78 cases (31.7%), combination therapies with antipsychotic and antidepressant drugs or with two or more APDs were considered responsible. Male sex and a diagnosis of mania were associated with significantly higher rates of severe DILI while older patients (≥65 years old) were significantly less often affected.. In the present analysis of a representative psychiatric inpatient cohort, olanzapine, perazine, and clozapine were the most common individual APDs associated with severe DILI.

Topics: Aged; Antidepressive Agents; Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Humans; Male; Pharmacovigilance

Topics: Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Humans

Clozapine is known as one of the atypical antipsychotics which is placed in the second line of medical treatment for schizophrenia due to its hematologic complications. It is used in cases of resistance to treatment. Some side effects of clozapine include leukopenia, granulocytopenia, fever, hepatotoxicity, sedation, dizziness, hypotension, weight gain, constipation, and seizure. Neutropenia and hepatotoxicity have been separately reported after taking atypical antipsychotics, including clozapine. However, simultaneous occurrence of these two complications is rare and has not been reported with clozapine use. This study reports a case of concurrent hepatotoxicity and neutropenia induced by clozapine. The patient was a 58-year-old man who started taking clozapine for the first time in March 2017, about seven weeks before his recent admission, because of a history of treatment-resistant schizophrenia. He had been referred to the emergency department of a general hospital with symptoms of weakness, lethargy, fever, and chills. The laboratory results showed neutropenia with a frequency of 352 × 103 (17.5%) and hepatotoxicity with alanine transferase (ALT) = 139 u/L, aspartate transferase (AST) = 214 u/L, total bilirubin = 11.5 mg/dL, and direct bilirubin = 9.3 mg/Dl, caused by taking clozapine. The symptoms were attenuated within eight days after discontinuation of clozapine. Moreover, the patient's para-clinical complications including neutropenia, and raised transaminases and bilirubin returned to normal. It was concluded that clozapine can simultaneously cause neutropenia and hepatotoxicity; physicians are recommended to be aware of this issue to prevent mortality through appropriate and timely diagnosis.

Topics: Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Humans; Lithium Carbonate; Male; Middle Aged; Neutropenia; Schizophrenia

Topics: Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Humans; Schizophrenia

Topics: Animals; Antipsychotic Agents; Carnitine; Cell Line; Chemical and Drug Induced Liver Injury; Clozapine; Disease Models, Animal; Dogs; Down-Regulation; Hep G2 Cells; Humans; Inhibitory Concentration 50; Kidney Tubules, Proximal; Lipid Metabolism; Liver; Madin Darby Canine Kidney Cells; Mice; Mice, Inbred ICR; Primary Cell Culture; Renal Reabsorption; Schizophrenia; Solute Carrier Family 22 Member 5; Toxicity Tests, Acute; Toxicity Tests, Chronic

This study was conducted to test the effects of schizandrin B (Sch B) on clozapine (CLZ) induced\ chronic liver injury in mice and the mechanism of action, and this may provide a new approach for clinical\ prevention of CLZ-induced side effects. The CLZ was given to mice for three weeks alone or co-administration\ with Sch B. The changes of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase\ (ALP) and antioxidation indexes superoxide dismutase (SOD), malonic dialdehyde (MDA), glutathione (GSH)\ and liver histological evaluation were determined. Expression of Nrf2 was assayed in hepatic cells by immunohistochemical\ staining and Western blotting. The changes of relative gene expression of NAD(P)H: quinone\ oxidoreductase l (NQO1) and heme oxygenase 1 (HO-1) were assayed by real-time Q-PCR. The results showed\ that pretreatment with a lower dosage of Sch B (25, 50 mg·kg−1) prevented CLZ-induced liver injury as indicated\ by the reduced levels of ALT, AST and ALP, and the preserved activities of SOD, GSH and inhibiting MDA. It\ was shown that Sch B could up-regulate Nrf2 expression leading to nuclear accumulation of Nrf2 to induce\ oxidative response genes such as NQO1 and HO-1. These results suggest that Sch B could protect against liver\ injury induced by CLZ via the activation of the Nrf2/ARE signal pathway in a dose-dependent manner.

Topics: Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clozapine; Cyclooctanes; Glutathione; Heme Oxygenase-1; Lignans; Liver; Malondialdehyde; Membrane Proteins; Mice; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Polycyclic Compounds; Protective Agents; Signal Transduction; Superoxide Dismutase

Chronic exposure to stress contributes to the etiology of mood disorders, and the liver as a target organ of antidepressant and antipsychotic drug metabolism is vulnerable to drug-induced toxicity. We investigated the effects of chronic administration of fluoxetine (15mg/kg/day) or clozapine (20mg/kg/day) on liver injury via the measurement of liver enzymes, oxidative stress and histopathology in rats exposed to chronic social isolation (21days), an animal model of depression, and controls. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the liver content of carbonyl groups, malonyldialdehyde (MDA), reduced glutathione (GSH), cytosolic glutathione S-transferase (GST) and nitric oxide (NO) metabolites were determined. We also characterized nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2) and CuZn-superoxide dismutase (CuZnSOD) protein expression as well as histopathological changes. Increased serum ALT activity in chronically-isolated and control animals treated with both drugs was found while increased AST activity was observed only in fluoxetine-treated rats (chronically-isolated and controls). Increased carbonyl content, MDA, GST activity and decreased GSH levels in drug-treated controls/chronically-isolated animals suggest a link between drugs and hepatic oxidative stress. Increased NO levels associated with NF-κB activation and the concomitant increased COX-2 expression together with compromised CuZnSOD expression in clozapine-treated chronically-isolated rats likely reinforce oxidative stress, observed by increased lipid peroxidation and GSH depletion. In contrast, fluoxetine reduced NO levels in chronically-isolated rats. Isolation induced oxidative stress but histological changes were similar to those observed in vehicle-treated controls. Chronic administration of fluoxetine in both chronically-isolated and control animals resulted in more or less normal hepatic architecture, while clozapine in both groups resulted in liver injury. These data suggest that clozapine appears to have a higher potential to induce liver toxicity than fluoxetine.

Topics: Alanine Transaminase; Animals; Antidepressive Agents; Antipsychotic Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clozapine; Cyclooxygenase 2; Fluoxetine; Glutathione; Glutathione Transferase; Liver; Male; Malondialdehyde; NF-kappa B; Nitric Oxide; Oxidative Stress; Rats, Wistar; Superoxide Dismutase

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Because of the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict IDILI in humans. According to the inflammatory stress hypothesis, the effects of inflammation interact with the effects of a drug or its reactive metabolite, precipitating toxic reactions in the liver. As a follow-up to our recently published mouse precision-cut liver slices model, an ex vivo model involving human precision-cut liver slices (hPCLS), co-incubated for 24 h with IDILI-related drugs and lipopolysaccharide (LPS), was developed to study IDILI mechanisms related to inflammatory stress in humans and to detect potential biomarkers. LPS exacerbated the effects of ketoconazole and clozapine toxicity but not those of their non-IDILI-related comparators, voriconazole and olanzapine. However, the IDILI-related drugs diclofenac, carbamazepine, and troglitazone did not show synergistic toxicity with LPS after incubation for 24 h. Co-incubation of ketoconazole and clozapine with LPS decreased the levels of glutathione in hPCLS, but this was not seen for the other drugs. All drugs affected LPS-induced cytokine release, but interestingly, only ketoconazole and clozapine increased the level of LPS-induced TNF release. Decreased levels of glutathione and cysteine conjugates of clozapine were detected in IDILI-responding livers following cotreatment with LPS. In conclusion, we identified ketoconazole and clozapine as drugs that exhibited synergistic toxicity with LPS, while glutathione and TNF were found to be potential biomarkers for IDILI-inducing drugs mediated by inflammatory stress. hPCLS appear to be suitable for further unraveling the mechanisms of inflammatory stress-associated IDILI.

Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Clozapine; Female; Humans; In Vitro Techniques; Ketoconazole; Lipopolysaccharides; Male; Middle Aged; Young Adult

Topics: Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Delusions; Humans; Male; Young Adult

Topics: Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Female; Humans; Middle Aged; Risk Factors; Schizophrenia, Paranoid

Inhibition of the activity of the human bile salt export pump (BSEP: ABCB11) has been proposed to play a role in drug-induced liver injury (DILI). To enhance understanding of the relationship between BSEP inhibition and DILI, inhibition of human BSEP (hBSEP) and its rat ortholog (rBsep) by 85 pharmaceuticals was investigated in vitro. This was explored using assays that quantified inhibition of ATP-dependent [(3)H]taurocholate uptake into inverted plasma membrane vesicles from Sf21 insect cells, which expressed the proteins. Of the pharmaceuticals, 40 exhibited evidence of in vitro transporter inhibition and overall a close correlation was observed between potency values for inhibition of hBSEP and rBsep activity (r(2) = 0.94), although 12 drugs exhibited >2-fold more potent inhibition of hBSEP than rBsep. The median potency of hBSEP inhibition was higher among drugs that caused cholestatic/mixed DILI than among drugs that caused hepatocellular or no DILI, as was the incidence of hBSEP inhibition with IC(50) <300 μM. All drugs with hBSEP IC(50) <300 μM had molecular weight >250, ClogP >1.5, and nonpolar surface area >180Å. A clear distinction was not evident between hBSEP IC(50) or unbound plasma concentration (C(max, u)) of the drugs in humans and whether the drugs caused DILI. However, all 17 of the drugs with hBSEP IC(50) <100 μM and C(max, u) >0.002 μM caused DILI. Overall, these data indicate that inhibition of hBSEP/rBsep correlates with the propensity of numerous pharmaceuticals to cause cholestatic DILI in humans and is associated with several of their physicochemical properties.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cell Line; Chemical and Drug Induced Liver Injury; Cholestasis; Drug-Related Side Effects and Adverse Reactions; Humans; Insecta; Rats; Risk Factors

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Decision Trees; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Liver; Pharmaceutical Preparations; Protein Binding

The human bile salt export pump (BSEP) is a membrane protein expressed on the canalicular plasma membrane domain of hepatocytes, which mediates active transport of unconjugated and conjugated bile salts from liver cells into bile. BSEP activity therefore plays an important role in bile flow. In humans, genetically inherited defects in BSEP expression or activity cause cholestatic liver injury, and many drugs that cause cholestatic drug-induced liver injury (DILI) in humans have been shown to inhibit BSEP activity in vitro and in vivo. These findings suggest that inhibition of BSEP activity by drugs could be one of the mechanisms that initiate human DILI. To gain insight into the chemical features responsible for BSEP inhibition, we have used a recently described in vitro membrane vesicle BSEP inhibition assay to quantify transporter inhibition for a set of 624 compounds. The relationship between BSEP inhibition and molecular physicochemical properties was investigated, and our results show that lipophilicity and molecular size are significantly correlated with BSEP inhibition. This data set was further used to build predictive BSEP classification models through multiple quantitative structure-activity relationship modeling approaches. The highest level of predictive accuracy was provided by a support vector machine model (accuracy = 0.87, κ = 0.74). These analyses highlight the potential value that can be gained by combining computational methods with experimental efforts in early stages of drug discovery projects to minimize the propensity of drug candidates to inhibit BSEP.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cell Line; Chemical and Drug Induced Liver Injury; Humans; Quantitative Structure-Activity Relationship

Idiosyncratic drug-induced liver injury (IDILI) has been the top reason for withdrawing drugs from the market or for black box warnings. IDILI may arise from the interaction of a drug's reactive metabolite with a mild inflammation that renders the liver more sensitive to injury resulting in increased toxicity (inflammatory stress hypothesis). Aiming to develop a robust ex vivo screening method to study inflammatory stress-related IDILI mechanisms and to find biomarkers that can detect or predict IDILI, mouse precision-cut liver slices (mPCLS) were coincubated for 24 h with IDILI-related drugs and lipopolysaccharide. Lipopolysaccharide exacerbated ketoconazole (15 μM) and clozapine (45 μM) toxicity but not their non-IDILI-related comparators, voriconazole (1500 μM) and olanzapine (45 μM). However, the other IDILI-related drugs tested [diclofenac (200 μM), carbamazepine (400 μM), and troglitazone (30 μM)] did not cause synergistic toxicity with lipopolysaccharide after 24 h of incubation. Lipopolysaccharide further decreased the reduced glutathione levels caused by ketoconazole or clozapine in mPCLS after 24 h of incubation, which was not the case for the other drugs. Lipopolysaccharide significantly increased nitric oxide (NO), cytokine, and chemokine release into the mPCLS media, while the treatment with the drugs alone did not cause any substantial change. All seven drugs drastically reduced lipopolysaccharide-induced NO production. Interestingly, only ketoconazole and clozapine increased the lipopolysaccharide-induced granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) release. Pilot experiments showed that diclofenac and troglitazone, but not carbamazepine, demonstrated synergistic toxicity with lipopolysaccharide after a longer incubation of 48 h in mPCLS. In conclusion, we have developed an ex vivo model to detect inflammatory stress-related liver toxicity and identified ketoconazole, clozapine, troglitazone, and diclofenac as drugs that showed synergistic toxicity with lipopolysaccharide. Reduced glutathione, G-CSF, and GM-CSF were identified to be potential biomarkers for IDILI-inducing drugs mediated by inflammatory stress, and mPCLS appear to be a promising screening tool to further unravel the mechanism of IDILI.

Topics: Animals; Benzodiazepines; Biomarkers; Carbamazepine; Cell Survival; Chemical and Drug Induced Liver Injury; Chemokines; Chromans; Clozapine; Cytokines; Diclofenac; Drug Synergism; Female; Glutathione; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; In Vitro Techniques; Ketoconazole; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Nitrogen Oxides; Olanzapine; Pyrimidines; Thiazolidinediones; Triazoles; Troglitazone; Voriconazole

Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for supporting drug discovery and biomarker development.

Topics: Animals; Benchmarking; Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; Drug Design; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Reproducibility of Results; United States; United States Food and Drug Administration

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automate

Topics: Animals; Chemical and Drug Induced Liver Injury; Cluster Analysis; Databases, Factual; Humans; MEDLINE; Mice; Models, Chemical; Molecular Conformation; Quantitative Structure-Activity Relationship

Drug-induced liver injury is a major issue of concern and has led to the withdrawal of a significant number of marketed drugs. An understanding of structure-activity relationships (SARs) of chemicals can make a significant contribution to the identification of potential toxic effects early in the drug development process and aid in avoiding such problems. This process can be supported by the use of existing toxicity data and mechanistic understanding of the biological processes for related compounds. In the published literature, this information is often spread across diverse sources and can be varied and unstructured in quality and content. The current work has explored whether it is feasible to collect and use such data for the development of new SARs for the hepatotoxicity endpoint and expand upon the limited information currently available in this area. Reviews of hepatotoxicity data were used to build a structure-searchable database, which was analyzed to identify chemical classes associated with an adverse effect on the liver. Searches of the published literature were then undertaken to identify additional supporting evidence, and the resulting information was incorporated into the database. This collated information was evaluated and used to determine the scope of the SARs for each class identified. Data for over 1266 chemicals were collected, and SARs for 38 classes were developed. The SARs have been implemented as structural alerts using Derek for Windows (DfW), a knowledge-based expert system, to allow clearly supported and transparent predictions. An evaluation exercise performed using a customized DfW version 10 knowledge base demonstrated an overall concordance of 56% and specificity and sensitivity values of 73% and 46%, respectively. The approach taken demonstrates that SARs for complex endpoints can be derived from the published data for use in the in silico toxicity assessment of new compounds.

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Humans; Structure-Activity Relationship; Tetracyclines; Thiophenes

The bile salt export pump (BSEP) is an efflux transporter, driving the elimination of endobiotic and xenobiotic substrates from hepatocytes into the bile. More specifically, it is responsible for the elimination of monovalent, conjugated bile salts, with little or no assistance from other apical transporters. Disruption of BSEP activity through genetic disorders is known to manifest in clinical liver injury such as progressive familial intrahepatic cholestasis type 2. Drug-induced disruption of BSEP is hypothesized to play a role in the development of liver injury for several marketed or withdrawn therapeutics. Unfortunately, preclinical animal models have been poor predictors of the liver injury associated with BSEP interference observed for humans, possibly because of interspecies differences in bile acid composition, differences in hepatobiliary transporter modulation or constitutive expression, as well as other mechanisms. Thus, a BSEP-mediated liver liability may go undetected until the later stages of drug development, such as during clinical trials or even postlicensing. In the absence of a relevant preclinical test system for BSEP-mediated liver injury, the toxicological relevance of available in vitro models to human health rely on the use of benchmark compounds with known clinical outcomes, such as marketed or withdrawn drugs. In this study, membrane vesicles harvested from BSEP-transfected insect cells were used to assess the activity of more than 200 benchmark compounds to thoroughly investigate the relationship between interference with BSEP function and liver injury. The data suggest a relatively strong association between the pharmacological interference with BSEP function and human hepatotoxicity. Although the most accurate translation of risk would incorporate pharmacological potency, pharmacokinetics, clearance mechanisms, tissue distribution, physicochemical properties, indication, and other drug attributes, the additional understanding of a compound's potency for BSEP interference should help to limit or avoid BSEP-related liver liabilities in humans that are not often detected by standard preclinical animal models.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Assay; Biological Transport; Cell Line; Cell Membrane; Chemical and Drug Induced Liver Injury; Cytoplasmic Vesicles; Drug Evaluation, Preclinical; Humans; Liver; Rats; Reproducibility of Results; Spodoptera; Transfection; Xenobiotics

Drug-induced liver injury (DILI) is one of the most important reasons for drug development failure at both preapproval and postapproval stages. There has been increased interest in developing predictive in vivo, in vitro, and in silico models to identify compounds that cause idiosyncratic hepatotoxicity. In the current study, we applied machine learning, a Bayesian modeling method with extended connectivity fingerprints and other interpretable descriptors. The model that was developed and internally validated (using a training set of 295 compounds) was then applied to a large test set relative to the training set (237 compounds) for external validation. The resulting concordance of 60%, sensitivity of 56%, and specificity of 67% were comparable to results for internal validation. The Bayesian model with extended connectivity functional class fingerprints of maximum diameter 6 (ECFC_6) and interpretable descriptors suggested several substructures that are chemically reactive and may also be important for DILI-causing compounds, e.g., ketones, diols, and α-methyl styrene type structures. Using Smiles Arbitrary Target Specification (SMARTS) filters published by several pharmaceutical companies, we evaluated whether such reactive substructures could be readily detected by any of the published filters. It was apparent that the most stringent filters used in this study, such as the Abbott alerts, which captures thiol traps and other compounds, may be of use in identifying DILI-causing compounds (sensitivity 67%). A significant outcome of the present study is that we provide predictions for many compounds that cause DILI by using the knowledge we have available from previous studies. These computational models may represent cost-effective selection criteria before in vitro or in vivo experimental studies.

Topics: Bayes Theorem; Chemical and Drug Induced Liver Injury; Humans; Ligands

Topics: Acute Disease; Adult; Antipsychotic Agents; Benzodiazepines; Chemical and Drug Induced Liver Injury; Clozapine; Hepatitis C, Chronic; Humans; Male; Olanzapine; Schizophrenia, Paranoid; Time Factors

Topics: Adult; Antipsychotic Agents; Biotransformation; Chemical and Drug Induced Liver Injury; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Isoxazoles; Liver Function Tests; Paliperidone Palmitate; Pyrimidines; Reference Values; Risperidone; Schizophrenia

Topics: Acute Disease; Adult; Antipsychotic Agents; Ascites; Chemical and Drug Induced Liver Injury; Clozapine; Female; Humans; Pleurisy; Psychotic Disorders; Serositis

Topics: Amoxicillin-Potassium Clavulanate Combination; Chemical and Drug Induced Liver Injury; Cholelithiasis; Cholestasis, Extrahepatic; Clozapine; Diagnosis, Differential; Gallstones; Humans; Lithium Compounds; Liver Function Tests; Male; Middle Aged; Periapical Abscess; Schizophrenia, Paranoid; Suicide, Attempted; Transaminases; Trichloroethylene

Topics: Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Drug Resistance; Eosinophilia; Exanthema; Female; Fever; Humans; Middle Aged; Schizophrenia

A case of clozapine-induced toxic hepatitis in a 49-year old woman with schizophrenia is described. The daily clozapine dose was clinically titrated to 300 mg. Subsequently, the patient experienced lethargy and anorexia, and fever, eosinophilia, leucocytosis and abnormal liver parameters were found. The serum concentration of clozapine was 8595 nmol/l, and treatment was discontinued. After eight days, the condition stabilised, and low-dose clozapine treatment was successfully reinstituted with serum monitoring (TDM).

Topics: Chemical and Drug Induced Liver Injury; Clozapine; Female; Humans; Middle Aged; Schizophrenia

Topics: Aged; Antiparkinson Agents; Antipsychotic Agents; Benzophenones; Chemical and Drug Induced Liver Injury; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Liver Function Tests; Neuroleptic Malignant Syndrome; Neurologic Examination; Nitrophenols; Tolcapone

Topics: Adult; Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Humans; Liver Diseases; Male; Seizures

This report describes a 48-year-old caucasian male with schizophrenia who developed hepatitis, hyperglycemia, pleural effusion, eosinophilia, hematuria and proteinuria early in clozapine treatment which resolved on drug discontinuation. The literature on similar cases is reviewed.

Topics: Antipsychotic Agents; Blood Cell Count; Chemical and Drug Induced Liver Injury; Clozapine; Eosinophilia; Hematuria; Humans; Hyperglycemia; Male; Middle Aged; Pleural Effusion; Proteinuria; Schizophrenia, Paranoid; Tomography, X-Ray Computed

Topics: Adult; Alanine Transaminase; Alkaline Phosphatase; Antipsychotic Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clozapine; gamma-Glutamyltransferase; Humans; L-Lactate Dehydrogenase; Liver Function Tests; Male; Middle Aged; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Chemical and Drug Induced Liver Injury; Clozapine; Dose-Response Relationship, Drug; Dystonia; Female; Humans; Schizophrenia, Paranoid

Agranulocytosis and hepatotoxic reactions are rare but severe side-effects of neuroleptic treatment. This article presents the case of a schizophrenic patient who concurrently developed agranulocytosis and acute hepatic drug reaction as a result of a combination of chemically different neuroleptic drugs. After restoration the patient was successfully treated with clozapine for six months without the hematologic disorders recurring.

Topics: Adult; Agranulocytosis; Antipsychotic Agents; Chemical and Drug Induced Liver Injury; Clozapine; Humans; Leukocyte Count; Male; Schizophrenia

Topics: Adult; Chemical and Drug Induced Liver Injury; Clozapine; Dose-Response Relationship, Drug; Humans; Male; Psychotic Disorders

Topics: Adult; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; L-Lactate Dehydrogenase; Liver Function Tests; Male; Recurrence; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Chemical and Drug Induced Liver Injury; Chronic Disease; Clozapine; Female; Humans; Liver Function Tests; Schizophrenia, Paranoid

During neuroleptic treatment with clozapine, transitory reversible rise in transaminases is not rare, while severe parenchymal damage with icterus has not previously been reported. Such a case is now described: a 54-year-old woman developed clozapine-induced cholestasis with severe liver damage.

Topics: Antipsychotic Agents; Biopsy; Chemical and Drug Induced Liver Injury; Cholestasis; Clozapine; Dibenzazepines; Female; Humans; Liver; Middle Aged

Topics: Acute Disease; Adult; Agranulocytosis; Bone Marrow; Chemical and Drug Induced Liver Injury; Clozapine; Dibenzazepines; Humans; Male; Schizophrenia

17 patients (13 males and 4 females) were examined for side effects due to long-term treatment with 8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo(b,e)(1,4)diazepine (clozapine) with emphasis on alterations in bone marrow, liver, and kidney function. 16 patients were schizophrenic, one patient was diagnosed psychosis e causa dubia. The age range was 25-68 years, with an average of 38.2 years. The daily clozapine dose varied from 225 to 800 mg with a total intake during the trial period of 149.1-891.6 g yielding an average of 479.8 g. The treatment period varied from 20 to 51 months, with an average of 35.9 months. None of the patients had to discontinue the treatment because of side effects. The laboratory data including hematological, and nephrological parameters revealed no significant changes related to clozapine treatment within the treatment period. No changes were observed in ECG. 12 patients experienced side effects, 8 of them receiving concomitant psycholeptic medication. 9 patients complained of temporary fatigue and 5 of these experienced continuous drowsiness. There were 8 cases of nocturnal hypersalivation and two cases of increased appetite. One patient developed light tachycardia and one patient orthostatic hypotension. Clozapine is known to be an effective anti-psychotic drug, but due to reports of agranulocytosis in 16 Finnish patients the drug was withdrawn from the Danish market in 1975 although later its use was merely restricted to special cases. This study does not indicate that clozapine contains greater risk of clinical side effects than commonly used psycholeptic drugs.

Topics: Adult; Aged; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Clozapine; Dibenzazepines; Female; Humans; Kidney Diseases; Male; Middle Aged; Psychotic Disorders; Time Factors

Topics: Adult; Alanine Transaminase; Alkaline Phosphatase; alpha-Amylases; Aspartate Aminotransferases; Bilirubin; Blood Sedimentation; Chemical and Drug Induced Liver Injury; Clozapine; Creatinine; Dibenzazepines; Female; gamma-Glutamyltransferase; Hematologic Diseases; Hemoglobins; Humans; L-Lactate Dehydrogenase; Leukocytes; Male; Middle Aged; Psychotic Disorders