PRECLINICAL TOXICOLOGY STUDIES WITH AZITHROMYCIN - GENETIC TOXICOLOGYEVALUATION

Azithromycin was subjected to a series of three in vitro and one in vi vo generic toxicology assays for the detection of drug-associated gene or chromosomal effects. In the Ames Salmonella typhimurium tester str ains TA1535, TA1537, TA98 and TA100, the presence of azithromycin was not associated with any increase in the number of his- revertants. Uri ne from mice dosed with up to 200 mg/kg of azithromycin also had no ef fect 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 L51 78Y/TK cells. Both the mammalian and microbial gene mutation assays in cluded the presence of rat-liver postmitochondrial (S9) fraction for t he detection of mutagenic biotransformation products. Mitogen-stimulat ed human lymphocytes cultured in the presence of 2.5-7.5 Ag/ml azithro mycin for 24 h or 30.0-40.0 mug/ml azithromycin for 3 h in the presenc e of rat S9 had chromosomal aberration frequencies that were no differ ent than negative control cells even though slight to moderate mitotic suppression was associated with these concentrations. In vivo assessm ent of this compound was completed in male and female mice with a sing le 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 mutation s in microbial or mammalian cells, or chromosomal aberrations in cultu red human lymphocytes or in mouse bone marrow in vivo.