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46 Pharmaceutical Technology ® Trends in Formulation 2022 eBook PharmTech.com Qualit y known (13, 14). One of the pathways for activation of N-nitrosoguanidines is believed to be a nucleophilic attack at the C=N to create a tetrahedral intermediate that eventually degrades to a diazotate [R-N=N-O-] ion. Neuclophiles like glutathione, which are abundant in vivo, can catalyze this kind of decomposition. T he probable decomposit ion of N-met hyl-N-n i- tro-N'-nitrosoguanidine is provided in Figure 3 (14). The other pathway may involve the generation of t he diazotate ion by a beta elim ination pat hway. This pathway could also generate isocyanates (13). Irrespective of the mechanism, the N-nitrosamides produce direct alkylating agents without the need of activation in presence of Cytochrome P450, and this differentiates them from N-nitrosamines. The com- pounds with N-nitrosoamide groups, if stable under physiological conditions, are known to be direct act- ing mutagens and in some cases, carcinogens. How- ever, it is noteworthy that many of the stable products of the nitrosourea class have shown anti-cancer po- tential and are APIs in chemotherapeutic drugs (e.g., carmustine, lomustine). The nitrosamines of several nitrosoguanidines including cimetidine have been found to be mutagenic based on several studies (15), but their carcinogenicity is in question. Also, many of these compounds, especially some nitrosoamides of primar y amines, are not stable under physiological conditions. Thus, during the risk evaluation of a N-nitrosamide, it needs to be evalu- ated if the N-nitrosoamides in question can thrive under physiological conditions. Mutagenicity and potency of N-nitrosoamides– are they the same as N-nitrosamines? While often included in discussions of nitrosamines, it needs to be recognized that the nitrosamides be- have quite differently in biological systems due to the fact that they are chemically unstable and inherently reactive and, unlike the N-nitrosoamines, can cause mutagenic events without first being metabolized (3,16,17). Many N-nitrosomonoalkylguanidines, N-ni- trosoalkylcarbamates, and N-nitrosomonoalkylureas are unstable, having half-lives at a biological pH of 7 ranging from a few minutes to a few hours. There are some notable exceptions to this instability; N-nitroso- dialkylureas are much more stable than the N-nitroso- monoalkylureas, having half-lives at pH 7 measured in days, and N-nitrosotrialkylureas are very stable, with half-lives measured in weeks or months (16). While not all of the nitrosamide compounds are carcinogenic (e.g., nitrosocimetidine), this class of compounds have the potential to be mutagenic in the absence of metabolic activation. As shown in Table I, the carcinogenic potency of the N-nitrosamides is ! "#$%&'!()!*+,,#-.'!,/&%0/%&',!+1!!!23#/&+,+!0+45+%36,7! ! ! ! ! ! ! "#$%&'!8)!90/#:;/#+3!+1!3#/&+,;4#6',!:'&,%,!3#/&+,;4#3',!<(=7!! ! ! ! ! ! ! "#$%&'!8)!90/#:;/#+3!+1!3#/&+,;4#6',!:'&,%,!3#/&+,;4#3',!<(=7!! FIGURE 2. Activation of nitrosamides versus nitrosamines (1).