Acute liver failure

Fontana, Robert J.; Quallich, Leonard G.

doi:10.1097/00001574-200105000-00013

Cited by 13 publications

(7 citation statements)

References 92 publications

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“…Hepatotoxicity is a common and potentially serious adverse response to drug exposure. For example, acetaminophen (paracetamol) can cause potentially life-threatening drug-induced hepatotoxicity (102,103). In a recent metabolomic study, male Sprague-Dawley rats were treated with three hepatotoxins, galactosamine, allyl alcohol, and acetaminophen, and both pre-and postdrug exposure urine samples were subjected to NMR analysis (38).…”

Section: Figurementioning

confidence: 99%

Metabolomics: A Global Biochemical Approach to Drug Response and Disease

Kaddurah‐Daouk

Kristal

Weinshilboum

2008

Annu. Rev. Pharmacol. Toxicol.

597

460

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Metabolomics is the study of metabolism at the global level. This rapidly developing new discipline has important potential implications for pharmacologic science. The concept that metabolic state is representative of the overall physiologic status of the organism lies at the heart of metabolomics. Metabolomic studies capture global biochemical events by assaying thousands of small molecules in cells, tissues, organs, or biological fluids-followed by the application of informatic techniques to define metabolomic signatures. Metabolomic studies can lead to enhanced understanding of disease mechanisms and to new diagnostic markers as well as enhanced understanding of mechanisms for drug or xenobiotic effect and increased ability to predict individual variation in drug response phenotypes (pharmacometabolomics). This review outlines the conceptual basis for metabolomics as well as analytical and informatic techniques used to study the metabolome and to define metabolomic signatures. It also highlights potential metabolomic applications to pharmacology and clinical pharmacology.

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Section: Figurementioning

confidence: 99%

Metabolomics: A Global Biochemical Approach to Drug Response and Disease

Kaddurah‐Daouk

Kristal

Weinshilboum

2008

Annu. Rev. Pharmacol. Toxicol.

597

460

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“…Therefore, many incidents of hepatotoxicity of various drugs have been reported (Biour et al 1998;Fontana and Quallich 2001;Ayonrinde et al 2005;Llinares Tello et al 2005). Attrition rates in the development of new drug candidates are still high due to adverse effects (Caldwell et al 2001;Cuatrecasas 2006;Smith and Schmid 2006).…”

Section: Introductionmentioning

confidence: 99%

Metabolomics and biomarker discovery: NMR spectral data of urine and hepatotoxicity by carbon tetrachloride, acetaminophen, and d-galactosamine in rats

Kim

Chung

et al. 2008

Metabolomics

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The primary objective of this study was to discover biomarkers which are correlated with hepatotoxicity induced by chemicals using 1 H NMR spectral data of urine. A procedure of nuclear magnetic resonance (NMR) urinalysis using pattern recognition was proposed for early screening of the hepatotoxicity of CCl 4 , acetaminophen (AAP), and D-galactosamine (GalN) in rats. The hepatotoxic compounds were expected to induce necrosis in hepatocytes. This was confirmed through blood biochemistry and histopathology. CCl 4 (1 ml/kg, po) or GalN (0.8 g/kg, ip) was single administered to Sprague-Dawley (S-D) rats and urine was collected every 24 h. Animals were sacrificed 24 h or 48 h post-dosing. AAP (2 g/kg, po) was administered for 2 days and then the animals were sacrificed 24 h after the last treatment. NMR spectroscopy revealed evidently different clustering between control groups and hepatotoxicant treatment groups in global metabolic profilings as indicated by partial least square (PLS)-discrimination analysis (DA). In targeted profilings, endogenous metabolites of allantoin, citrate, taurine, 2-oxoglutarate, acetate, lactate, phenylacetyl glycine, succinate, phenylacetate, 1-methylnicotinamide, hippurate, and benzoate were selected as putative biomarkers for hepatoxicity by CCl 4 , AAP, and GalN. Comparison of our rat 1 H NMR PLS-DA data with histopathological changes suggests that 1 H NMR urinalysis can be used to predict hepatotoxicity induced by CCl 4 , AAP, and GalN.

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“…Hepatotoxicity is a common and potentially serious adverse reaction to drugs such as acetaminophen (paracetamol). 132,133 In this metabolomic study, male Sprague-Dawley rats were treated with acetaminophen, and both preand postdrug exposure urine samples were subjected to NMR analysis. 134 A model was then developed that used predrug metabolomic data to predict both ratios of acetaminophen glucuronide conjugate to parent drug and postacetaminophen hepatotoxicity (class 1, no or minimal hepatic necrosis, to class 3, moderate necrosis).…”

Section: Genome-wide and Systems Biology Studiesmentioning

confidence: 99%

Pharmacogenomics: a systems approach

Wang

2010

WIREs Mechanisms of Disease

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Pharmacogenetics and pharmacogenomics involve the study of the role of inheritance in individual variation in drug response, a phenotype that varies from potentially life-threatening adverse drug reactions to equally serious lack of therapeutic efficacy. Pharmacogenetics-pharmacogenomics represents a major component of the movement to `individualized medicine'. Pharmacogenetic studies originally focused on monogenic traits, often involving genetic variation in drug metabolism. However, contemporary studies increasingly involve entire `pathways' that include both pharmacokinetics (PKs)—factors that influence the concentration of a drug reaching its target(s)—and pharmacodynamics (PDs), factors associated with the drug target(s), as well as genome-wide approaches. The convergence of advances in pharmacogenetics with rapid developments in human genomics has resulted in the evolution of pharmacogenetics into pharmacogenomics. At the same time, studies of drug response are expanding beyond genomics to encompass pharmacotranscriptomics and pharmacometabolomics to become a systems-based discipline. This discipline is also increasingly moving across the `translational interface' into the clinic and is being incorporated into the drug development process and governmental regulation of that process. The article will provide an overview of the development of pharmacogenetics-pharmacogenomics, the scientific advances that have contributed to the continuing evolution of this discipline, the incorporation of transcriptomic and metabolomic data into attempts to understand and predict variation in drug response phenotypes as well as challenges associated with the `translation' of this important aspect of biomedical science into the clinic.

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Acute liver failure

Cited by 13 publications

References 92 publications

Metabolomics: A Global Biochemical Approach to Drug Response and Disease

Metabolomics: A Global Biochemical Approach to Drug Response and Disease

Metabolomics and biomarker discovery: NMR spectral data of urine and hepatotoxicity by carbon tetrachloride, acetaminophen, and d-galactosamine in rats

Pharmacogenomics: a systems approach

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