Drug Metabolism and Reactive Metabolites

Drug Metabolism and Reactive Metabolite Formation in Hepatocytes. 294... 

FIGURE 16.4 General scheme for the role played by reactive drug metabolites in causing a variety of adverse reactions. The reactive metabolites usually account for only a small fraction of total drug metabolism and are too unstable to be chemically isolated and analyzed. In many cases, covalent binding of these metabolites to tissue macromolecules only occurs after their formation exceeds a critical threshold that overcomes host detoxification and repair mechanisms. 

A number of chemicals with demonstrable suppression of immune function produce this action via indirect effects. By and large, the approach that has been most frequently used to support an indirect mechanism of action is to show immune suppression after in vivo exposure but no immune suppression after in vitro exposure to relevant concentrations. One of the most often cited mechanisms for an indirect action is centered around the limited metabolic capabilities of immunocompetent cells and tissues. A number of chemicals have caused immune suppression when administered to animals but were essentially devoid of any potency when added directly to suspensions of lymphocytes and macrophages. Many of these chemicals are capable of being metabolized to reactive metabolites, including dime-thylnitrosamine, aflatoxin Bi, and carbon tetrachloride. Interestingly, a similar profile of activity (i.e., suppression after in vivo exposure but no activity after in vitro exposure) has been demonstrated with the potent immunosuppressive drug cyclophosphamide. With the exception of the PAHs, few chemicals have been demonstrated to be metabolized when added directly to immunocompetent cells in culture. A primary role for a reactive intermediate in the immune suppression by dimethylnitrosamine, aflatoxin Bi, carbon tetrachloride, and cyclophosphamide has been confirmed in studies in which these xenobiotics were incubated with suspensions of immunocompetent cells in the presence of metabolic activation systems (MASs). Examples of MASs include primary hepatocytes, liver microsomes, and liver homogenates. In most cases, confirmation of a primary role for a reactive metabolite has been provided by in vivo studies in which the metabolic capability was either enhanced or suppressed by the administration of an enzyme inducer or a metabolic inhibitor, respectively. 

Castro-Perez, J.M., Applications of quadrupole time-of-flight mass spectrometry in reactive metabolite screening, in Mass Spectrometry in Drug Metabolism and Pharmacokinetics, Ramanathan, R. (ed.), John Wiley Sons, Hoboken, NJ, 159, 2008. 

Fig. 1 Relationship between drug metabolism and toxicity. Toxicity may accrue through accumulation of parent drug or, via metabolic activatirai, through formation of a chemically reactive metabolite, which, if not detoxified, can effect covalent modification of biological macromolecules. The identity of the target macromolecule and the functional consequence of its modification...

Wen, B., Ma, L., Rodrigues, A.D., et al. (2008) Detection of novel reactive metabolites of trazodone evidence for CYP2D6-mediated bioactivation of m-chlorophenylpiperazine. Drug Metabolism and Disposition, 36, 841-850. 

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