Mutagenicity of the new quinolone antibacterial agent levofloxacin.
A new quinolone antibacterial agent (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6- carboxylic acid hemihydrate (levofloxacin, DR-3355, CAS 100986-85-4), was studied for mutagenicity using the following short-term in vitro and in vivo tests. 1.


METHODS
reverse mutation test (Ames method) on S. typhimurium and E. coli; and HGPRT forward mutation test, cytogenetic test, and sister chromatid exchange (SCE) test, all on Chinese hamster cells. 2. In vivo studies: mouse micronucleus test, SCE test on mouse bone marrow cell, in vivo-in vitro unscheduled DNA synthesis (UDS) test on rat primary hepatocytes, and dominant lethal test in BDF1 mice. In the in vitro tests for SCE and for chromosomal aberration, DR-3355 gave dose-dependent positive responses, but no mutagenicity was observed in the same indicators of the in vivo studies, even at the maximum tolerated doses. This strongly suggested that DR-3355 would have no mutagenic effects when used in the treatment of infectious diseases. DR-3355 did not show any positive response in the reverse mutation test, the HGPRT mutation test, the in vivo-in vitro UDS test or the dominant lethal test. These results suggest that chemotherapy with DR-3355 should have no mutagenic effect in man.
Shimada
H
H
Drug Safety Research Center, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Itoh
S
S
Hattori
C
C
Tada
S
S
Matsuura
Y
Y
D000818:Animals; D000890:Anti-Infective Agents / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002869:Chromosome Aberrations; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D005260:Female; D064704:Levofloxacin; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D015242:Ofloxacin / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D012854:Sister Chromatid Exchange / Q000187:drug effects
D000890:Anti-Infective Agents; D009153:Mutagens; D064704:Levofloxacin; D004247:DNA; D015242:Ofloxacin