erythromycin-estolate and Chemical-and-Drug-Induced-Liver-Injury

Topics: Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Chloramphenicol; Erythromycin Estolate; Humans; Isoniazid; Rifampin; Tetracyclines; Troleandomycin

Topics: Autoantibodies; Chemical and Drug Induced Liver Injury; Cholestasis; Erythromycin; Erythromycin Estolate; Erythromycin Ethylsuccinate; Humans; Liver; Liver Function Tests; Recurrence

The chemistry, bioavailability, and adverse effects of erythromycin base, stearate, estolate, and ethylsuccinate are reviewed. Criteria for the evaluation of erythromycin bioavailability studies include study design, patient population, meal composition and timing, and assay methodology. Based on these criteria, the bioavailability of individual erythromycin products are evaluated in this paper. Compared with other antibiotics, the erythromycins have a good safety record. However, both the estolate and ethylsuccinate forms of erythromycin may cause hepatotoxity. Considering bioavailability and adverse effect data, a specific brand of enteric-coated erythromycin base tablets is recommended for erythromycin-sensitive infections in adults. For pediatric patients, a liquid formulation of erythromycin estolate or erythromycin ethylsuccinate is recommended.

Topics: Administration, Oral; Biological Availability; Chemical and Drug Induced Liver Injury; Dosage Forms; Erythromycin; Erythromycin Estolate; Humans

Topics: Adult; Aged; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Cyclohexanecarboxylic Acids; Erythromycin; Erythromycin Estolate; Humans; Liver; Middle Aged; Staphylococcal Infections

Drug-induced liver injury (DILI) accounts for 20-40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound- and/or patient-specific. Compound-specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energy-dependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR-LTKB), the inhibitory properties of 24 Most-DILI-, 28 Less-DILI-, and 20 No-DILI-concern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs.. These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Chemical and Drug Induced Liver Injury; Humans; Male; Mitochondria, Liver; Rats; Rats, Sprague-Dawley; Severity of Illness Index

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 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

Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, was investigated for its possible hepatoprotective effect in Wistar rats against erythromycin estolate-induced toxicity. Oral administration of THC significantly prevented the occurrence of erythromycin estolate-induced liver damage. The increased level of serum enzymes (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP)), bilirubin, cholesterol, triglycerides, phospholipids, free fatty acids and plasma thiobarbituric acid reactive substances (TBARS) and hydroperoxides observed in rats treated with erythromycin estolate were very much reduced in rats treated with THC and erythromycin estolate. This biochemical observation were supplemented by histopathological examination of liver section. Results of this study revealed that THC could afford a significant protection against erthromycin estolate-induced hepatocellular damage. Tetrahydrocurcumin had a better protective effect when compared with Silymarin, a reference drug.

Topics: Administration, Oral; Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bilirubin; Butylated Hydroxytoluene; Chemical and Drug Induced Liver Injury; Cholesterol; Curcumin; Erythromycin Estolate; Fatty Acids, Nonesterified; Female; Glutathione; Lipid Peroxides; Phospholipids; Rats; Rats, Wistar; Silymarin; Thiobarbiturates; Triglycerides

Livex, a compound herbal formulation, was investigated for its possible hepatoprotective effect in Wistar rats against erythromycin estolate induced toxicity. Oral administration of Livex significantly prevented the occurrence of erythromycin estolate induced hepatic damage. The increased level of serum enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase), bilirubin, serum and tissue cholesterol, triglycerides, phospholipids and free fatty acids observed in rats treated with erythromycin estolate were very much reduced in rats treated with Livex and erythromycin estolate. These biochemical observations were supplemented by histopathological examination of liver sections. Results of this study revealed that Livex could afford a significant protection against erythromycin estolate induced hepatocellular damage.

Topics: Administration, Oral; Alanine Transaminase; Alkaline Phosphatase; Animals; Anti-Bacterial Agents; Aspartate Aminotransferases; Bilirubin; Chemical and Drug Induced Liver Injury; Erythromycin Estolate; Lipids; Liver; Male; Plant Extracts; Plants, Medicinal; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar

Topics: Chemical and Drug Induced Liver Injury; Erythromycin Estolate; Female; History, 20th Century; Humans; Troleandomycin

Topics: Adult; Chemical and Drug Induced Liver Injury; Erythromycin Estolate; Female; Humans

Topics: Chemical and Drug Induced Liver Injury; Erythromycin; Erythromycin Estolate; Humans

The possibility that endotoxin pretreatment could prevent the hepatotoxic effects of erythromycin estolate (EE) was investigated using the isolated perfused rat liver. The addition of E. coli endotoxin (25 micrograms/ml) to the perfusate, 30 min prior to EE administration at 150 or 200 microM, significantly ameliorated the decreases in bile and perfusate flow caused by either concentrations of the drug in control liver preparations. This phenomenon was also studied using liver isolated from rats pretreated in vivo with endotoxin for three days. In these preparations, EE at both concentrations did not alter bile flow and caused reductions of perfusate flow which were far less than those observed in untreated control livers. Furthermore, in livers from endotoxin-treated rats EE induced less reduction of bile acid excretion and, at 150 microM, it did not increase the bile to perfusate ratio of sucrose seen in control preparations after the drug, which may be an expression of altered hepatocytic membrane permeability. Since it is known that both endotoxin and EE interact with membranes, it is suggested that the "protective" effects of endotoxin may occur at the membrane level.

Topics: Animals; Bile; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Endotoxins; Erythromycin; Erythromycin Estolate; Escherichia coli; Kinetics; Liver Diseases; Male; Rats; Rats, Inbred Strains

An unusual cause of a cholescintigraphic, false-positive, erythromycin-induced hepatotoxicity is presented. This occurred in the presence of preservation of hepatic uptake and the normal appearance of gut activity. Serial scintigraphy and serum chemistries documented underlying gallbladder normalcy.

Topics: Acute Disease; Adult; Chemical and Drug Induced Liver Injury; Cholecystitis; Diagnosis, Differential; Erythromycin; Erythromycin Estolate; False Positive Reactions; Female; Humans; Imino Acids; Liver; Radionuclide Imaging; Technetium; Technetium Tc 99m Disofenin

Topics: Adult; Chemical and Drug Induced Liver Injury; Cholestasis; Erythromycin; Erythromycin Estolate; Female; Humans

Using primary cultures of parenchymal hepatocytes as a model system, the cytotoxic potential of dantrolene sodium (DS) was compared with that of erythromycin estolate (EE)--a known hepatotoxin. Parallel morphological and functional comparisons were made, following 4-, 8-, or 24-h exposures of hepatocyte cultures, using phase contrast microscopy and lactate dehydrogenase (LDH) leakage, respectively. Four-hour exposures of cultures to rather low concentrations of EE (i.e. 50 microM) resulted in cellular necrosis and significantly elevated LDH release. As the concentration of this hepatotoxin was increased, the changes were more pronounced. However, even 4- or 8-h exposures of cultures to a maximum of 100 microM DS did not affect LDH leakage or morphological integrity, although marginally detectable morphological changes did not occur at the highest concentration after 24-h. The value of using primary parenchymal hepatocyte cultures as a model system for the assessment of xenobiotic-induced hepatotoxicity was confirmed.

Topics: Animals; Cell Survival; Cells, Cultured; Chemical and Drug Induced Liver Injury; Dantrolene; Erythromycin; Erythromycin Estolate; L-Lactate Dehydrogenase; Liver; Rats; Rats, Inbred Strains

The effects of erythromycin estolate, a well known hepatotoxic macrolide antibiotic, on isolated rat hepatocyte viability and on subcellular Ca2+ transport have been investigated. Erythromycin estolate (0.5 mM), but not erythromycin base and erythromycin ethylsuccinate, induced 100% cell death after 60 min incubation, and caused maximal inhibition of mitochondrial and microsomal Ca2+ sequestration activities at 0.1 mM concentration. Sodium lauryl sulphate, which is the surfactant moiety of the erythromycin estolate molecule, caused effects similar to those exhibited by erythromycin estolate. Disorders of the intracellular calcium homeostasis seem to play a role in the lauryl sulphate-mediated hepatotoxic action of erythromycin estolate.

Topics: Animals; Calcium; Chemical and Drug Induced Liver Injury; Erythromycin; Erythromycin Estolate; Homeostasis; In Vitro Techniques; Male; Microsomes, Liver; Mitochondria, Liver; Rats; Rats, Inbred Strains

Two patients experienced hepatotoxicity associated with erythromycin estolate (Ilosone) usage, followed 13 and 15 years later by an hepatotoxic reaction with administration of erythromycin ethylsuccinate (E.E.S.). These cases provide further evidence for erythromycin ethylsuccinate-associated hepatotoxicity and demonstrate erythromycin cross-sensitivity after previous erythromycin estolate liver injury. Hepatotoxicity to both sensitivity after previous erythromycin estolate liver injury. Hepatotoxicity to both estolate and ethylsuccinate preparations of erythromycin stimulates speculation regarding the potentially hepatotoxic moiety of the erythromycin molecule. Furthermore, these cases suggest that all erythromycin preparations should be avoided or used only with careful monitoring in patients with previous erythromycin-associated liver injury.

Topics: Adult; Aged; Chemical and Drug Induced Liver Injury; Dermatitis; Erythromycin; Erythromycin Estolate; Erythromycin Ethylsuccinate; Female; Humans; Liver; Male; Respiratory Tract Infections

Topics: Chemical and Drug Induced Liver Injury; Erythromycin; Erythromycin Estolate; Humans; Nausea; Vomiting

Topics: Aspartate Aminotransferases; Blood Glucose; Chemical and Drug Induced Liver Injury; Clinical Enzyme Tests; Diabetes Complications; Drug Interactions; Erythromycin; Erythromycin Estolate; Female; Humans; Hydrochlorothiazide; Hypertension; Liver Diseases; Middle Aged; Pneumonia

Topics: Chemical and Drug Induced Liver Injury; Child; Erythromycin; Erythromycin Estolate; Humans; Risk

Topics: Chemical and Drug Induced Liver Injury; Erythromycin; Erythromycin Estolate; Legislation, Drug; Male; United States; United States Food and Drug Administration

Topics: Adult; Chemical and Drug Induced Liver Injury; Erythromycin; Erythromycin Estolate; Female; Humans; Liver

Topics: Chemical and Drug Induced Liver Injury; Erythromycin; Erythromycin Estolate

Topics: Chemical and Drug Induced Liver Injury; Child; Erythromycin; Erythromycin Estolate; Humans; United States; United States Food and Drug Administration

Topics: Chemical and Drug Induced Liver Injury; Child, Preschool; Erythromycin; Erythromycin Estolate; Female; Humans

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Erythromycin; Erythromycin Estolate; Humans; Infant; Middle Aged; Staphylococcal Infections; Streptococcal Infections

Topics: Alkaline Phosphatase; Bilirubin; Chemical and Drug Induced Liver Injury; Clinical Enzyme Tests; Drug Hypersensitivity; Erythromycin; Erythromycin Estolate; Hepatitis A; Jaundice; Liver Diseases; Liver Function Tests; Sodium Dodecyl Sulfate; Toxicology; Transaminases

Topics: Biopsy; Chemical and Drug Induced Liver Injury; Erythromycin; Erythromycin Estolate; Hepatitis; Hepatitis A; Liver Function Tests; Surgical Procedures, Operative; Toxicology