Comparative nitrosation of etintidine and cimetidine

Abstract

Etintidine (4), a new histamine H2-receptor antagonist, was compared with cimetidine (1) for susceptibility to in vitro nitrosation at pH 1 and pH 3. Each agent formed two mono-N-nitrosoguanidine derivatives: N-cyano-N′-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethyl}-N″-nitroso-N″-(2-propynyl)guanidine (5) and N-cyano-N′-{2-[5-methyl-1H-imidazol-4-yl)methylthio]ethyl}- N′-nitroso-N″-(2-propynyl)guanidine (6) from etintidine and N-cyano-N′-methyl-N″-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethyl}- N′-nitrosoguanidinc (2) and N-cyano-N′-methyl-N"-{2-[(5-methyl-1H-imidazol-4-yl)methyl-thio]ethyl}-N′-nitrosoguanidine (11) from cimetidine. The N-nitroso derivative 5 from etintidine cyclized to 2-cyanoimino-3-{2-((5-methyl-1H-imidazol-4-yl)methylthio]ethyl}-N″-methylene-1-nitroso-imidazoline (7) at neutral or basic pH's. Both agents were nitrosated less at pH 3 than at pH 1, and at both pH's nitrosation of etintidine was considerably less than that of cimetidine. At pH 1, with a nitrite concentration about 150–500 times that expected in fasting human gastric juice, formation of 5 and 6 from etintidine was barely detectable (each < 0.5%). Comments are made on the standard WHO conditions for investigating nitrosation of drugs.

Estimation of nizatidine gastric nitrosatability and product toxicity via an integrated approach combining HILIC, in silico toxicology, and molecular docking

“…This indicates that neither pepsin nor NaCl has enhancing effect on the nitrosation of NZ, where the main factor controlling it is the pH. This pH-dependent nitrosation behavior agreed with that of cimetidine which increased by 6.8 folds at pH 1.0 relative to pH 3.0 [ 26 ].…”

“…This effect was attributed to the nitroso derivatives of these H 2 -antagonists formed in the stomach [ 47 ]. Being guanidine derivatives, these H 2 -antagonists are highly nitrosatable at low-pH medium [ 48 ], however, a considerable nitrosation is also occurred at higher pH that may be experienced in vivo during treatment with these H 2 -antagonists as demonstrated in our experiments at pH 3.5 and in the published literature [ 26 ]. It is worthy to note that some proton pump inhibitors such as omeprazole were associated with an increased risk of cancer, but, unlike H 2 -antagonists, this effect was attributed to elevation of the gastric pH to a level optimum for nitrosation of other endogenous precursors and proliferation of bacteria that catalyzes the nitrosation reaction, rather than undergoing nitrosation themselves [ 49 ].…”

Characterization of the Solution Degradation Products of Etintidine, An H2-Receptor Antagonist

“…This cyclization occurred over the entire pH range (2)(3)(4)(5)(6)(7)(8) which was investigated. The amine 4a (Scheme I) resulted from both nitrile hydrolysis and cyclization processes, while the cyanoarnine 4b (Scheme I) resulted from only cyclization.…”