Mutagenicity study of the new cephalosporin antibiotic cefditoren pivoxil
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1Pharmaceutical Research Center, Meiji Seika Kaisha Ltd., Yokohama, Japan.
Abstract:
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.
Insights
Cefditoren pivoxil (CDTR-PI) showed mutagenicity in a Chinese hamster cell test due to formaldehyde generation. However, it is unlikely to be mutagenic or carcinogenic in clinical use.
Area of Science:
- Pharmacology and Toxicology
- Genetics and Molecular Biology
Background:
- Cefditoren pivoxil (CDTR-PI) is a cephalosporin antibiotic.
- Assessing the mutagenicity and carcinogenicity of pharmaceutical compounds is crucial for clinical safety.
Purpose of the Study:
- To evaluate the mutagenicity of cefditoren pivoxil (CDTR-PI) using a comprehensive battery of in vitro and in vivo tests.
- To investigate the potential source of observed clastogenicity and assess the implications for clinical use.
Main Methods:
- Conducted bacterial reverse mutation assay, chromosomal aberration tests (CHL cells, human lymphocytes), micronucleus test (mice), HGPRT gene mutation test (L5178Y cells), unscheduled DNA synthesis test (rat stomach mucosa), and cell transformation test (BALB/3T3 cells).
- Analyzed metabolites for clastogenicity and monitored for formaldehyde generation in culture media.
- Reviewed existing data on formaldehyde carcinogenicity.
Main Results:
- CDTR-PI induced structural chromosomal aberrations in CHL cells at concentrations ≥150 µg/ml, attributed to formaldehyde release from the pivoxil moiety.
- No mutagenic or clastogenic effects were observed in other tests, including in vivo assays, even at high doses.
- Formaldehyde, the identified clastogen, has shown no carcinogenicity in long-term oral studies in rats.
Conclusions:
- The clastogenicity observed in vitro is likely due to formaldehyde generated from CDTR-PI, not the parent compound itself.
- Based on the comprehensive testing and formaldehyde's established safety profile, CDTR-PI is unlikely to exhibit mutagenicity or carcinogenicity under clinical conditions.