Dear all,
I’d like to know your opinion regarding the potential formation of API-like nitrosamines for carbamazepine.
Considering the API impurities, iminostilbene, and iminodibenzyl, would they be nitrosated if exposed to the ideal conditions and generate N-nitroso iminostilbene and N-nitroso iminodibenzyl?
And if so, these nitrosamines would be mutagenic and carcinogenic?
I understand that since these molecules cannot undergo alfa-hydroxylation, due to the lack of alfa-hydrogens in the molecules, it could be proposed the absence of mutagenicity/carcinogenicity by this pathway, but what if they can be mutagenic and carcinogenic by other mechanisms?
@letsfco Thanks for the inquiry and sharing the information. I would let @fernandaw@David provide their expert comment but I’m sure the whole community would argue that the lack of alpha-hydrogen can suggest a lower risk.
That been said, I found couple articles that might be interesting for the discussion (sorry they are both in German)
There is a proven mechanism of nitrosation in the molecule Drugs from the classes of tricyclic antidepressives and antiepileptics, nitrosatable under simulated human gastric conditions
[Article in German] D Ziebarth1, T Schramm, A Töppel
Abstract
The nitrosatability of Pryleugan (imipramine), Herphonal (trimipramine), and Finlepsin (carbamazepine) was investigated under simulated human gastric conditions using a colorimetric measuring method. All of them proved to be nitrosatable even at very low nitrite concentrations. In the presence of ascorbic acid, the formation of N-nitroso compounds under model conditions was inhibited markedly. N-nitroso-dihydrodibenzazepine and N-nitroso-dibenzazepine could be identified by thin layer chromatography as main products. The biological effects of these N-nitroso compounds are not known up to now.
The AMES test is reported negative Microbial mutagenicity testing of N-nitrosoiminostilbene and N-nitrosoiminodibenzyl, the nitrosation products of the drugs carbamazepine and trimipramine hydrochloride
[Article in German] D Ziebarth1, T Schramm, R Braun
Abstract
The active agents of the drugs Finlepsin and Herphonal, carbamazepine and trimipramine, were nitrosated under simulated human gastric conditions. For both formed N-nitroso compounds, N-nitroso iminostilbene (N-nitroso-5H-dibenz(b,f)azepine) and N-nitroso iminodibenzyl (N-nitroso-10,11-dihydro-5H-dibenz(b,f)azepine), tests for mutagenic potency in the Ames-test gave negative results.
I can’t comment as to formation, however am not at all surprised by the reported negative Ames.
nitrosoiminostilbene is an aromatic nitrogen; even were there to be alpha hydrogens these do not undergo the dealkylation since it would be breaking open an aromatic ring. There is a potential alternative mechanism for these analogous to that for C-nitrosated aromatics (essentially this is reduction to the hydroxylamine and they drop into the aromatic amine mechanism of action), however with this sterically hindered position I think that doubtful - it is known that the mutagenicity due to aromatic amines is affected by steric hindrance.
nitrosoiminodibenzyl, while an aliphatic nitrogen, does have two aromatic substituents. Alpha-hydroxylation is impossible, and while a potential alternative mechanism comparable to that for nitrosodiphenylamine exists (a) nitrosodiphenylamine is an exceptionally weak carcinogen, and (b) I would expect the potential for that mechanism to be structure-specific. In the absolute worst case I would argue for read-across to nitrosodiphenylamine…
Dear David, thank you so much!! Your rationale is the same that we were discussing internally in my company. However, with your expertise, we are more confident to defend this rationale!
