{IARC MONOGRAPHS VOLUME 24 A-NITHUSATALLE DRUGS

: . aan . - og eet d
The other class of substrate, amines, are present, with both catalysts and inhibit Table 2 (contd)

food, Drugs may also contain nitrosatable amines,

> Drug N-Nitroso compound formed Reference

trosation of drugs ; wl N-Nitrosodimethylamine Lijinsky (1 974);
: . oobS Mirvish (1975)
Lijinsky et af. (1972b,c) showed that amine-containing drugs may react with nitrite?"

form N-nitroso compounds. As would be expected, reactivity varies considerably within] -’Methapyritene N-Nitrosodimethylamine

Lijinsky (1974);

s grour of chemicals. A selection of relevant data is given in Table

Table 2. Some N-nitroso compounds formed from drugs

2. eo

Tt

” Mirvish (1975)

_ Quinacrine A-Nitrosodiethylamine

Lijinsky (1974);
Mirvish (1975)

Drug

N-Nitresa compound formed

Reference

Piperazine

Phenmetrazine

Ephedrine

Ethambutot

Chtordiazepoxide
Phenacetin

Aminophenazona

Oxytetracycline
Chlorpromazine
Dextropropoxyphene

Chiorpheniramine

Mono- and dinitrosopiperazine

N-Nitrosophenmetrazine

N-Nitrosoephedrine |

‘

Dinitrosoethambutol

N-Nitrosoderivative and rearrangement
Products ‘

N-Nitroso-2-nitro-4-ethoxyacet-
anilide and other products

N-Nitrosodimethylamine

N-Nitrosodimethylamine
N-Nitrosodimethylamine
N-Nitrosodimathylamine

N-Niwosodimethylamine

 Mlevish (1975)

Greenblatt et a/, (1972);
Mirvish (1975)

Wogan et a/, (1975);

-Elsenbrand et af. (1978);

Kinawi & Schuster
(1978)

Moniesano et a/. (1974)

Walser et af, (1074);
Mirvish (1975)

Eisenbrand &
Preussmann (1975)

Lijinsky et af. (1972b)

LUjinsky er af. (1972b);
Lifinsky (1974)

LiJinsky (1974);
Mirvish (1975)

Lijinsky (1974);
Mirvish (1975)

LiJinsky (1974);
Mirvish (1975)

Lucanthone N-Nitrosodiethylamine Lilinsky (1974);

Minish (1975)

Tolazamide N-Nitrosohexsmathylenalmine Lilinsky et af. (1972p);

Lijinsky (1974)
Cyclizine

Dinitrosopiparazine LiJinsky (1974);

Mirvish (1975)

Tripelennamine A-Nitrosodemethyltripelennamine Rao & Krishna (1975)

Disulfiram N-Nitrosodiethylamine and N-nitroso- Lilinsky et af. (1972b)
piperidine

'

7 Nikethamide N-Nitrosodlethylamine and M-nitroso-

Lijinsky et af, (1972b)}
piperidine

It follows from these and similar data that most drugs that contain tertiary amino- or
N‘N-dialkylamido-groups react only very slowly under conditions of pH and temperature
similar to those of the human stomach. Lijinsky (1974) investigated the nitrosatability
of 12 drugs under defined conditions (in most cases: 5 mg of the drug per mi, 10 mg
nitrite per ml, pH 3.4, 37°C, 4 hours! reaction time) and found that the yield of N-nitroso
compounds was below 1% in almost all cases. Higher reactivity was seen with the oral anti-
diabetic drug tolazamide (3.4% fleld of N-nitrosohexamethyleneimine, 3 hours’ reaction
time, pH 3.1), the antibiotic oxytetracycline (15% N-nitrosodimethylamine, 8 mo/ml
drug, 16 mg/m! nitrite, PH 3) and the analgesic drug aminophenazone (amidopyrine, amino-
pyrine) (40% A-nitrosodimethylamine, 0.25 mg/m! drug, 0.25 mg/ml nitrite, 2 hours’
reaction time, pH 3.2). Tripelennamine, under similér conditions, yielded 6% N-nitroso-
demethy! compound {Rao & Krishna, 1975).