For definition of Groups, see Preamble Evaluation.
VOL.: 50 (1990) (p. 235)
CAS No.:
Chemical Abstr. Name: Guanidine N-cyano-N'-methyl-N"-(2-{[(5-methyl-1H-imidazol-
4-yl)methyl]thio}ethyl)-
Cimetidine is a histamine H2-receptor antagonist which inhibits gastric acid secretion. Since its introduction in the mid-1970s, it has been used widely by oral administration for the treatment of duodenal and gastric ulcers.
Although cimetidine can be nitrosated in vitro in the presence of nitrite under acidic conditions to form N-nitrosocimetidine, no study in experimental animals or in humans has demonstrated that this reaction occurs in vivo.
Cimetidine was tested for carcinogenicity by oral administration in single studies in mice, rats and dogs. In the experiment in mice, dams were treated throughout life beginning two weeks prior to pregnancy, with no increase in tumour incidence. In female progeny that were exposed throughout life from conception, there was an increase in the incidence of lymphomas, although these tumours also occurred at relatively high rates in control animals. In rats, an increase in the incidence of benign Leydig-cell tumours of the testis was observed in the low- and high-dose groups but not in the mid-dose group. The study in dogs was inadequate for evaluation.
In a study in which mice were exposed from conception throughout life to a combination of cimetidine and sodium nitrite, males had an increased incidence of lung neoplasms, although these tumours also occurred at a high frequency in control animals.
N-Nitrosocimetidine was tested for carcinogenicity by oral administration in mice and rats and by skin application in mice. The experiments in rats and three of the studies in mice were inadequate for evaluation. In one study by oral administration in mice, there was no increase in the incidence of tumours.
In a large number of case reports, cancer, particularly gastric cancer, was diagnosed at various intervals after the start of cimetidine therapy. These reports are difficult to interpret because gastric cancer is a common malignancy and cimetidine is a commonly used drug, and coincidence cannot be ruled out.
Three cohort studies showed increased incidences of gastric cancer but also of other gastrointestinal cancers among cimetidine users; however, as for the case reports, the association could well have been due to the drug being given for symptoms of pre-existing cancers. This interpretation is supported by a diminution of the association with increasing duration of follow-up. Two of the studies also showed an association between cimetidine use and lung cancer, but confounding with cigarette smoking could well have been the explanation.
Cimetidine has been associated with reversible impotence and other antiandrogenic effects in men.
N-Nitrosocimetidine is rapidly converted to cimetidine in vivo in experimental animals.
Cimetidine did not induce single-strand breaks in DNA from rats treated in vivo, nor did it methylate DNA in a variety of tissues of rats in vivo. It did not induce single-strand breaks in the DNA of rat cells treated in vitro. Cimetidine was not mutagenic to and did not cause DNA damage in Salmonella typhimurium or Escherichia coli. Cimetidine hydrochloride induced single-strand breaks and unscheduled DNA synthesis in rat but not human cells in vitro. It did not cause sister chromatid exchange in human cells in vitro.
Cimetidine in combination with sodium nitrite did not induce DNA damage in vivo or methylate DNA in a variety of tissues of rats in vivo. Gastric juice from cimetidine-treated patients was mutagenic to bacteria when enriched with nitrite.
N-Nitrosocimetidine has not been demonstrated in gastric juice of humans; however, increased gastric concentrations of nitrite and total N-nitroso compounds have been reported in some studies of patients taking cimetidine. N-Nitrosocimetidine induced DNA damage, sister chromatid exchange, chromosomal aberrations and morphological transformation in mammalian cells in vitro and caused DNA damage and mutation in bacteria. Radiolabelled N-nitrosocimetidine methylated DNA in a variety of tissues of rats in vivo.
There is inadequate evidence for the carcinogenicity of cimetidine in humans.
There is inadequate evidence for the carcinogenicity of cimetidine in experimental animals.
Cimetidine is not classifiable as to its carcinogenicity to humans (Group 3).
For definition of the italicized terms, see Preamble Evaluation.
See Also:
Toxicological Abbreviations