Download Drug-Induced Liver Disease by Neil Kaplowitz, Laurie D. DeLeve PDF

By Neil Kaplowitz, Laurie D. DeLeve

Epidemiological stories have came across that medications at the moment are the most typical explanation for liver failure within the usa, and the previous decade has noticeable an explosion of recent details about the immunology, toxicology, and pharmacology of drug-induced liver disorder. This expertly written moment version offers an in-depth dialogue of the new advancements in drug-induced hepatotoxicity, masking mechanisms, histopathology, administration, danger elements, and styles of drug and toxin-induced liver affliction.

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Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 2004; 17(1):3–16. 63. Qiu Y, Benet LZ, Burlingame AL. Identification of the hepatic protein targets of reactive metabolites of acetaminophenin in vivo in mice using two-dimensional gel electrophoresis and mass spectrometry. J Biol Chem 1998; 273(28):17940–53. 64. Nelson SD, Dahlin DC, Rauckman EJ, et al. Peroxidase-mediated formation of reactive metabolites of acetaminophen.

Iyer R, Coles B, Raney KD, et al. DNA adduction by the potent carcinogen aflatoxin B1: mechanistic studies. J Am Chem Soc 1994; 116(5):1603–9. 68. Johnson WW, Guengerich FP. Reaction of aflatoxin B1 exo-8,9-epoxide with DNA: kinetic analysis of covalent binding and DNA-induced hydrolysis. Proc Natl Acad Sci USA 1997; 94(12):6121–5. 69. Johnson WW, Ueng Y-F, Mannervik B, et al. Conjugation of highly reactive aflatoxin B1 8,9-exoepoxide catalyzed by rat and human glutathione transferases: estimation of kinetic parameters.

This aspect can be done without radiolabeled material. Quantitation of in vivo (animal) results is done subsequently, with radiolabeled drug. A rough decision cutoff value of 50 pmol adduct/mg protein has been proposed (62), but obviously this value would be a function of dose, time, etc. The overall plan in these strategies is to find better and earlier biomarkers that can be used effectively in the development process and even in clinical trials and marketed drugs. A critical issue with candidates found in animals is extrapolation to humans.

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