Reactive species, metabolism, fate

Metabolism studies on hydrazines alkylated at one position have also been performed in vivo 84). Iproniazid, which is structurally related to isoniazid, was shown to be metabolized to reactive components which became covalently bound to hepatic tissue. The radiolabel was contained in the isopropyl moiety (555). The proposed metabolic fate of iproniazid is also illustrated in Fig. 17. The major difference between these activation pathways is that the reactive species formed metabolically from isoniazid is an acylating agent while in the case of iproniazid an alkylating agent is formed. 

The metabolic fate of NO gives rise to a further series of compounds, collectively known as the reactive nitrogen species (RNS). However, the consequences of many of the chemical reactions involving RNS in vivo and, particularly, in growing tumors are not known. 

Biotransformation and generation of reactive intermediate metabolites are associated with a variety of toxicities and idiosyncratic reactions.37 Toxicologists should always consider how drug disposition and fate contribute to toxicity, as target organ dosimetry, biotransformation, and detoxification reactions can be important determinants of toxicity. In all cases, understanding how biotransformation may differ across species, with emphasis on human metabolism, is an important component in determining whether preclinical effects are predictive of and relevant for human safety evaluation. 

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