Hepatotoxicity drug-induced

Park, B.K. et al. 2005. The role of metabolic activation in drug-induced hepatotoxicity. Annu. Rev. Pharmacol. Toxicol. 45 177. 

Of course, Rezulin is nof fhe only drug implicated in liver toxicity. In fact, the FDA recently posted a nottce on its website (http //fda.gov/), describing a special interesf and monitoring of drug-induced hepatotoxicity ... 

The reader should note the emphasis in the above paragraphs drug-induced hepatotoxicity is the leading cause of acute liver failure and the number one reason for regulatory actions against drugs in the United States ... 

Shah RR. Drug-induced hepatotoxicity pharmacokinetic perspectives and strategies for risk reduction. Adverse Drug React Toxicol Rev 1999 18 181-233. 

Liver injury is clinically defined as an increase of serum alanine amino transferase (ALT) levels of more than three times the upper limit of normal and a total bilirubin level of more than twice the upper limit of normal [4]. The clinical patterns of liver injury can be characterized as hepatocellular (with a predominant initial elevation of ALT), cholestatic (with an initial elevation of alkaline phosphatase) or mixed. The mechanisms of drug-induced hepatotoxicity include excessive generation of reactive metabolites, mitochondrial dysfunction, oxidative stress and inhibition of bile salt efflux protein [5]. Better understandings of these mechanisms in the past decades led to the development of assays and models suitable for studying such toxic mechanisms and for selecting better leads in the drug discovery stage. 

I 75 Predicting Drug-Induced Hepatotoxicity In Vitro, In Silica and In Vivo Approaches... 

Serum chemistry markers play an important role in hepatotoxicity evaluation in human and animal safety studies. The classic markers of hepatotoxicity are alanine aminotransferase (ALT), aspartate aminotrasnferase (AST) and alkaline phosphatase (ALP) [124—127]. Drug-induced hepatotoxicity can be difficult to assess in some circumstances. Hepatotoxic responses can be intrinsic (predictable, dose-related) or idiosyncratic (unpredictable, non-dose-related). ALT, AST and ALP are generally not useful for predicting idiosyncratic responses. The administration of some drugs, such as isoniazid, can lead to a high incidence of ALT elevation, but are tolerated by most patients without severe hepatotoxicity. Adverse drug reactions can be masked... 

Drug-induced hepatotoxicity can present in variable manifestations, such as cell death (necrosis, apoptosis), infiammation, degeneration (steatosis), fibrosis/cirrho-sis and the development of tumors. The manifestations of drug toxicity may not be mutually exclusive and may occur sequentially, or in combination. ALT and ALP can be used to generally classify the pattern of liver injury as either hepatocellular (ALT >3x ULN), cholestatic (ALP >2x ULN, ALT/ALP <2) or mixed (elevated ALP and ALT). The successful monitoring of hepatotoxicity would identify cases before irreversible injury occurs. The activity levels of ALT, AST and ALP only increase after hepatic or cholestatic injury has occurred. Waiting for activity levels to exceed the established thresholds may be too late [3]. New biomarkers are needed to monitor/predict the specific sequence of events for different classes of hepatotoxic compounds. 

EMEA (2008) Non-dinical Guideline on Drug-Induced Hepatotoxicity, http //www.emea.europa.eu/pdfs/ human/swp/15011506en.pdf... 

Blomme, E.A., Yang, Y. and Waring, J.F. (2009) Use of toxicogenomics to understand mechanisms of drug-induced hepatotoxicity during drug discovery and development. Toxicol. Lett., 186 (1), 22-31. 

Pre-existing liver disease In general patients with pre-existing liver disease are not at increased risk of drug-induced hepatotoxicity exceptions to this include methotrexate and sodium valproate... 

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