COMPARATIVE MUTAGENICITY TESTING OF CEFTIOFUR SODIUM .1. POSITIVE RESULTS IN IN-VITRO CYTOGENETICS

Preclinical safety evaluation of new drugs is routine prior to the use in humans or animals and genetic toxicology assays are an accepted pa rt of the evaluation along with other more traditional measures of tox icity. A widely used battery of genetic toxicology assays includes an Ames Salmonella microsome assay, a mammalian cell mutation assay, a ra t bone marrow micronucleus test and an in vitro assay for induction of chromosomal aberrations. Ceftiofur (U-64279E, NAXCEL (R), EXCENEL (R) ), a new generation cephalosporin antibiotic, was subjected to this ba ttery of assays. The result of the first three (Ames test, V79/HPRT ma mmalian cell mutation assay and the micronucleus test) were negative, the in vitro assay for induction of chromosome aberrations in CHO cell s gave positive results. The nature of the observed aberrations was pr imarily chromatid and isochromatid breaks, gaps and fragments with lit tle evidence of chromosomal rearrangements in the absence of S9 metabo lic activation. The aberration increase was only seen following an ext ended (44 h) exposure to drug, no evidence of clastogenic activity was seen in the presence of S9 metabolic activation or at shorter treatme nt times. The severe treatment conditions required to produce the clas togenic effects also produced very high levels of mitotic inhibition a nd thus the observation of chromosomal aberrations is unlikely to be b iologically meaningful.