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GENERAL CONSIDERATIONS ON W-NITROSATABLE DRUGS W HO,TARC.
vol. 24- ;
. September (190

introduction

Many N-nitroso compounds (nitrosamines and nitrosarmides) have been shown to be
carcinogenic in experimental animals (SARC, 1978). The formation of N-nitroso
compounds is theoretically possible with all compounds that contain amino groups, Secon-
dary amines react directly; tertiary and, in some cases, primary amines may react by more
complicated mechanisms. Since the endogencus formation of N-nitroso compounds from
nitrosatable amine precursors and nitrose<ing agents, such as nitrite or nitrous gases, is not
usually taken into account In carcinogenicity tests of the parent compound, additional

investigations are necessary to evaluate this possible hazard,

The possibility that \-nitroso compounds are formed /n. vivo was first discussed by
Druckrey & Preussmann (1962) and was first demonstrated in animal experiments by
Sander & Birkle (1969). Several detailed reviews on the subject are available (Mirvish,
1975; WHO, 1977; IARC, 1978; Olajos & Coulston, 1978; WHO, 1978).

Chemistry of N-nitrosation

The formation of nitrosamines from secondary amines and nitrite at acid pH can be
described by the following equation:

R, R,
NH + NaNO, N— NA? ana’ + OH

7 | ara |

R;

.

In reality, the chemistry of this reaction is much more complicated (Ridd, 1961;
Challis & Butler, 1968; Fridman et a/,, 1971). For amines, the effective nitrosating agent is
Ny O;, which is formed from nitrite in acidic aqueous media. Only the free, unprotonated
amine, and not the amine salt, Is available for. nitrosation. As a result, the reaction rate is
heavily dependent on pH: low pH favours formation of N,Q, from nitrite, but also favours
protonation of the amine; at higher pH free amine is available, but N,0, formation is
reduced. !t follows that the nitrosation of basic amines shows a pH optimum (usually pH
3.0-3.5) and is dependent on the basicity (pKa) of the amine.