PRECLINICAL TOXICOLOGY STUDIES WITH AZITHROMYCIN - GENETIC TOXICOLOGY EVALUATION

Azithromycin was subjected to a series of three in vitro and one in vivo generic toxicology assays for the detection of drug-associated gene or chromosomal effects. In the Ames Salmonella typhimurium tester strains TA1535, TA1537, TA98 and TA100, the presence of azithromycin was not associated with any increase in the number of his- revertants. Urine from mice dosed with up to 200 mg/kg of azithromycin also had no effect on the number of revertants in these same strains suggesting the absence of mutagenic excretory products following oral exposure. When tested up to the cytotoxic level of 240 mug/ml, azithromycin caused no increase in the mutant frequency at the thymidine kinase locus of L5178Y/TK cells. Both the mammalian and microbial gene mutation assays included the presence of rat-liver postmitochondrial (S9) fraction for the detection of mutagenic biotransformation products. Mitogen-stimulated human lymphocytes cultured in the presence of 2.5-7.5 Ag/ml azithromycin for 24 h or 30.0-40.0 mug/ml azithromycin for 3 h in the presence of rat S9 had chromosomal aberration frequencies that were no different than negative control cells even though slight to moderate mitotic suppression was associated with these concentrations. In vivo assessment of this compound was completed in male and female mice with a single oral dose of 200 mg/kg followed by sacrifice at 6, 24 or 48 h later and metaphase analysis of bone marrow for chromosomal aberrations. No statistically significant elevations of chromosomally aberrant cells were found. We conclude that azithromycin does not cause gene mutations in microbial or mammalian cells, or chromosomal aberrations in cultured human lymphocytes or in mouse bone marrow in vivo.