Human Drug-induced Liver Injury Research Articles

Possible Drug-Induced Hepatopathy in a Dog Receiving Zonisamide Monotherapy for Treatment of Cryptogenic Epilepsy

A 9-year old female spayed Rottweiler was diagnosed with cryptogenic epilepsy and started on zonisamide monotherapy (8.3 mg/kg, PO, q 12 hr). Three weeks after the 1st dose of zonisamide the dog presented for vomiting, inappetence and icterus. Serum biochemistry showed marked elevation of liver enzymes, consistent with hepatocellular damage and cholestasis. No underlying cause for liver disease was identified and a drug-induced hepatopathy was suspected. Zonisamide was discontinued and replaced by potassium bromide. Supportive therapy consisted of intravenous fluids, antiemetics, antibiotics and hepatoprotectants. The dog made a complete recovery and serial serum biochemical examinations showed complete normalisation of liver parameters 8 weeks after discontinuation of zonisamide. Based on a human Drug-induced Liver Injury Diagnostic Scale, the likelihood for zonisamide-induced hepatopathy was classified as "possible". Veterinary practitioners and owners should be educated about the potential for an idiosyncratic drug reaction to zonisamide. If signs of hepatotoxicity are recognised early and zonisamide is discontinued, complete recovery is possible.

IL-4 mediates dicloxacillin-induced liver injury in mice

Drug-induced liver injury (DILI) is a major problem in drug development and clinical drug therapy. In most cases, the mechanisms are still unknown. It is difficult to predict DILI in humans due to the lack of experimental animal models. Dicloxacillin, penicillinase-sensitive penicillin, rarely causes cholestatic or mixed liver injury, and there is some evidence for immunoallergic idiosyncratic reaction in human. In this study, we investigated the mechanisms of dicloxacillin-induced liver injury. Plasma ALT and total-bilirubin (T-Bil) levels were significantly increased in dicloxacillin-administered (600 mg/kg, i.p.) mice. Dicloxacillin administration induced Th2 (helper T cells)-mediated factors and increased the plasma interleukin (IL)-4 level. Neutralization of IL-4 suppressed the hepatotoxicity of dicloxacillin, and recombinant mouse IL-4 administration (0.5 or 2.0 μg/mouse, i.p.) exacerbated it. Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is a cognate receptor for prostaglandin (PG) D 2, and is suggested to be involved in Th2-dependent allergic inflammation. We investigated the effect of 13,14-Dihydro-15-keto-PGD 2 (DK-PGD 2; 10 μg/mouse, i.p.) administration on dicloxacillin-induced liver injury. DK-PGD 2/dicloxacillin coadministration resulted in a significant increase of alanine aminotransferases and a remarkable increase of macrophage inflammatory protein 2 expression. In conclusion, to the best of our knowledge, this is the first report to demonstrate that dicloxacillin-induced liver injury is mediated by a Th2-type immune reaction and exacerbated by DK-PGD 2.

A Predictive Ligand-Based Bayesian Model for Human Drug-Induced Liver Injury

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.

Immunoallergic Drug-Induced Liver Injury in Humans

No conclusive data exist that define the mechanisms of idiosyncratic drug-induced liver injury (DILI) in humans; therefore, we are forced to speculate based on their clinical characteristics. The major characteristics are most easily explained by an immune mechanism. Many cases of idiosyncratic DILI tend to have a longer delay in onset and sometimes do not occur rapidly on rechallenge. These instances of DILI have been attributed to metabolic idiosyncrasy. However, these characteristics may also reflect an autoimmune mechanism, and most drugs that cause idiosyncratic DILI are also associated with various types of other autoimmune reactions. A characteristic feature of the immune system is that different individuals respond differently to the same immunogen. In some cases, a drug can induce an immune response to a reactive metabolite acting as a hapten; in others, the response is against a native protein, which leads to an autoimmune reaction. This is likely responsible for the interindividual differences in susceptibility and outcome noted in human DILI.

ヒト肝細胞キメラマウス（PXBマウス）を用いたヒト薬物性肝障害発現の評価

ヒト肝細胞キメラマウス（PXBマウス）を用いたヒト薬物性肝障害発現の評価

Prediction of drug-induced liver injury in humans by using in vitro methods: The case of ximelagatran

Objective: To investigate the possible mechanisms underlying the liver enzyme elevations seen during clinical studies of long-term treatment (>35 days) with ximelagatran, and investigate the usefulness of pre-clinical in vitro systems to predict drug-induced liver effects.Methods: Ximelagatran and its metabolites were tested for effects on cell viability, mitochondrial function, formation of reactive metabolites and reactive oxygen species, protein binding, and induction of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) gene expression or nuclear orphan receptors. Experimental systems included fresh and cryopreserved hepatocytes, human hepatoma cell lines (HepG2 and HuH-7) and subcellular human liver fractions.Results: Loss of cell viability was only seen in HepG2 cells at ximelagatran concentrations ⩾100μM and in cryopreserved human hepatocytes at ⩾300μM, while HuH-7 cells were not affected by 24h exposure at up to 300μM ximelagatran. Calcium homeostasis was not affected in HepG2 cells exposed to ximelagatran up to 300μM for 15min. There was no evidence for the formation of reactive metabolites when cell systems were exposed to ximelagatran. ALT and AST expression in human hepatoma cell lines were also unchanged by ximelagatran. Mitochondrial functions such as respiration, opening of the transition pore, mitochondrial membrane depolarization and β-oxidation were not affected by ximelagatran or its metabolites.Conclusion: Ximelagatran at concentrations considerably higher than that found in plasma following therapeutic dosing had little or no effect on cellular functions studied in vitro. The in vitro studies therefore did not elucidate the mechanism by which ximelagatran induces liver effects in humans, possibly because of limitations in the experimental systems not reflecting characteristics of the human hepatocyte, restricted exposure time, or because the primary mechanism for the observed clinical liver effects is not on the parenchymal liver cell.