Mutagenicity study of the new cephalosporin antibiotic cefditoren pivoxil.
The mutagenicity of a cephalosporin antibiotic, (-)-(6R,7R)-2,2-dimethylpropionyloxymethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2- (4-methylthiazol-5-yl) ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (cefditoren pivoxil, CAS 117467-28-4, CDTR-PI), was evaluated by various mutagenicity tests as follows: the reverse mutation assay in bacteria, the chromosomal aberration test with Chinese hamster CHL cells, the micronucleus test with mice, the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus gene mutation test with L5178Y cells, the chromosomal aberration test with human lymphocytes, the unscheduled DNA synthesis test with rat stomach mucosa cells, and the cell transformation test with BALB/3T3 cells. CDTR-PI induced the structural chromosomal aberrations considered direct action in the chromosomal aberration test with CHL cells at concentrations of 150 micrograms/ml and more, but in none of the other mutagenicity tests even in excessive doses. Evaluation for clastogenicity with metabolites of CDTR-PI and checking for formaldehyde generation in the culture medium appeared to verify that the original source of the clastogenicity of this antibiotic was a formaldehyde generated from a pivoxil radical of CDTR-PI. The carcinogenicity of formaldehyde has been reported as negative in rats administered orally for 2 years. These results suggested the CDTR-PI would reveal neither mutagenicity nor carcinogenicity under clinical conditions.
Shindo
Y
Y
Pharmaceutical Research Center, Meiji Seika Kaisha Ltd., Yokohama, Japan.
Hayashi
H
H
Ando
M
M
Tatebayashi
T
T
D016475:3T3 Cells / Q000187:drug effects; D000818:Animals; D002460:Cell Line / Q000187:drug effects / Q000648:ultrastructure; D002511:Cephalosporins / Q000633:toxicity*; D002869:Chromosome Aberrations; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000648:ultrastructure; D051379:Mice; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D002511:Cephalosporins; D009153:Mutagens; C057710:cefditoren pivoxil; D004247:DNA