Drug metabolism and hepatotoxicity.

Publisher Summary This chapter discusses the drug metabolism and hepatotoxicity. Drug metabolism has become the comfortable generic term describing metabolism of all foreign compounds, xenobiotics or chemicals with no nutritive value (anutrients). Interindividual variability in drug metabolic activity arises from genetic variability, physiological modulation and the influence of diet, disease and environmental agents such as other drugs. The same variability can be expected to apply to the generation of reactive and potentially hepatotoxic metabolites from therapeutic agents. However, the ability of these potential toxins to trigger sequences of key events mediating cell damage and dysfunction adds a further layer of variable complexity which determines outcome. The summation of these multiple variables probably underlies the idiosyncratic nature of the majority of hepatotoxins. Recognition of a drug-related etiology continues to be a challenging diagnostic step given the variable pathology induced, however by enabling early drug withdrawal this frequently limits the severity of any evolving damage. Mechanistically-based interventions show the greatest promise in management of emerging toxicity, however clinically safe and effective regimens are surprisingly rare. Given the lengthy and costly development programs for new drugs and the wastefulness of subsequent drug withdrawal, the use of mechanistically-based antidotes incorporated within medications may be a way forward for reducing the potential toxicity of invaluable additions to the pharmacopeia.