Stability of Reactive Metabolites

For compounds that require metabolic activation, avoiding structural features that may provide resonance stabilization of electrophilic metabolites (e.g., conjugated double bonds, or conjugated system/aryl moiety) will decrease the lifetime of the reactive intermediates. 

Stability and Transport of Reactive Metabolites. In tissues incapable of activating IPO, no tissue damage and little alkylation is seen. This, coupled with the evidence for in situ activation discussed above, indicates that the alkylating metabolite(s) is too reactive and/or unstable to escape the site of activation and circulate to other tissues. 

In contrast to the lability of certain dN adducts formed by the BHT metabolite above, amino acid and protein adducts formed by this metabolite were relatively stable.28,29 The thiol of cysteine reacted most rapidly in accord with its nucleophilic strength and was followed in reactivity by the a-amine common to all amino acids. This type of amine even reacted preferentially over the e-amine of lysine.28 In proteins, however, the e-amine of lysine and thiol of cysteine dominate reaction since the vast majority of a-amino groups are involved in peptide bonds. Other nucleophilic side chains such as the carboxylate of aspartate and glutamate and the imidazole of histidine may react as well, but their adducts are likely to be too labile to detect as suggested by the relative stability of QMs and the leaving group ability of the carboxylate and imidazole groups (see Section 9.2.3). 

Introduction of substituent(s) adjacent to the electrophilic group, or of bulky substituent(s) on the molecule of attachment, will minimize its carcinogenic/ mutagenic potential. This is because the nature and position of substituents may influence electronic or steric effects on the bioactivation and reactivity/stability of many ultimate electrophilic metabolites. 

Toxicity is a major cause for the withdrawal of drugs from the market and it is a major concern for pharmaceutical researchers. Reactive metabolism is certainly a very hot topic within the whole approach to drug metabolism. The downstream consequences of not identifying reactive metabolites may be financially catastrophic. There is an increasing drive to have early prediction of the metabolic fate and interactions of candidate drug molecules. Factors such as metabolic stability, toxic metabolite production, and P450 inhibition and induction are all routinely monitored to prevent compounds with poor pharmacokinetic properties from progressing forward onto clinical trials. 

Spin traps come in basically two types nitroso compounds and nitrone compounds. Reactive free radicals react with the carbon of the nitrone functional group to form a radical adduct that always has a nitroxide group, which is an unusually stable type of free radical. Nitrones are the most useful spin traps for the in vivo detection of free radical metabolites because of the stability of the resulting radical adduct. However, identification of the parent radicals can be difficult because adducts derived from different radicals often have very similar EPR spectra. A comprehensive review of this area through 1992 has recently been published [48]. 

Thus, the mode of action of many teratogens is different and is not fully understood. The mechanism depends on several factors, such as bioactivation of toxicants, the stability of toxicants or their reactive metabolites to reach the embryo, and biotransformation or the detoxifying capability of the embryonic tissues. 

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