Phototoxic Fluoroquinolones  
 

Return to Phototoxic Pesticides
Abstracts

KEYWORDS:
photocarcinogenic, photocarcinogenicity
photoclastogenic
photocytotoxic
photogenotoxic
photohemolytic
photomutagenic
, photomutagenicity
phototoxic, phototoxicity

       
       
Bay Y3118
Ciprofloxacin
Clinafloxacin
Enoxacin
Fleroxacin
Gemifloxacin
Grepafloxacin
Levofloxacin
Lomefloxacin
Moxifloxacin
Norfloxacin
Ofloxacin
Pefloxacin
Sitafloxacin
Sparfloxacin
Temafloxacin
Tosufloxacin
Trovafloxacin

 


Name: Bay Y3118
CAS No. 144194-96-7
Formula: C20-H21-Cl-F-N3-O3.Cl-H
Structure:
Other Names:

Bay y 3118
Bay-Y3118

Class Fluoroquinolone
Effects
(some, not all)
• Photogenotoxic
• Phototoxic
 
Use: na

Bay Y3118 Abstracts:

Recent reports on the photochemical carcinogenicity and photochemical genotoxicity of fluoroquinolone antibacterials led to an increasing awareness for the need of a standard approach to test for photochemical genotoxicity. In this study the micronucleus test using V79 cells was adapted to photogenotoxicity testing. Results of using different UVA/UVB relationships enabled us to identify a suitable irradiation regimen for the activation of different kinds of photosensitizers. Using this regimen, 8-methoxypsoralen and the fluoroquinolones lomefloxacin, grepafloxacin and Bay Y 3118 were identified to cause micronuclei and toxicity upon photochemical activation.
Ref: The application of the micronucleus test in Chinese hamster V79 cells to detect drug-induced photogenotoxicity; by B Kersten et al. Mutat Res 1999 Sep 15;445(1):55-71.

... After exposure to 10 and 30 mg Bay y 3118, a dose-dependent induction of damage to the mtDNA was found, whereas exposure to 3 and 1 mg showed no effect. NDEA (25 mg) was used as positive control.
Ref: Damage to mitochondrial DNA induced by the quinolone Bay y 3118 in embryonic turkey liver. By H Enzmann et al. Mutat Res 1999 Apr 6;425(2):213-24

Name: Ciprofloxacin
CAS No. 85721-33-1
Formula: C17-H18-F-N3-O3  
Structure:  
Other Names:

Too many to list:
Commonly known as Cipro

Class Fluoroquinolone (Carboxyfluoroquinoline)
Effects
(some, not all)
Photogenotoxic
Photohemolytic
• Potential to induce cartilage lesions in juvenile rats
• Chondrotoxicity
 
Significantly impaired both testicular function and structure in rats. 
Retarded fracture healing in rats
Use(s):

Antibacterial
Anti-infective agent

A Carboxyfluoroquinoline antimicrobial agent that is effective against a wide range of microorganisms. It has been successfully and safely used in the treatment of resistant respiratory, skin, bone, joint, gastrointestinal, urinary, and genital infections.

Ciprofloxacin Abstracts:

AIM: To compare two methods of measuring DNA damage induced by photogenotoxicity of fluoroquinolones (FQ).
METHODS: Lomefloxacin (LFLX), sparfloxacin (SPFX), ciprofloxacin (CPFX), and levofloxacin (LELX) were tested by comet assay and photodynamic DNA strand breaking activity under the different conditions of UVA irradiation.
RESULTS: In comet assay, photogenotoxicity was evident at SPFX 1 mg/L
, LFLX 5 mg/L, and CPFX 5 mg/L, and LELX 10 mg/L. In photodynamic DNA strand-breaking activity, SPFX and LFLX induced the conversion of the supercoiled form into the nicked relaxed form at 10-50 micromol/L, while CPFX at 25 micromol/L and LELX at 50 micromol/L.
CONCLUSION: There were good correlations between the two methods to detect DNA damage induced by phototoxicity of fluoroquinolones. Photodynamic DNA strand breaking activity was a good method to detect DNA damage induced by photogenotoxicity of fluoroquinolones as well as comet assay.

Ref: Compare two methods of measuring DNA damage induced by photogenotoxicity of fluoroquinolones. By Zhang T, Li JL, Xin J, Ma XC, Tu ZH. Acta Pharmacol Sin. 2004 Feb;25(2):171-5.

Ofloxacin and ciprofloxacin are two closely-related fluoroquinolones which both induce chondrotoxicity in juvenile dogs. In immature rats, however, cartilage lesions have been described with ofloxacin only...We conclude that ciprofloxacin an N-Methyl-ciprofloxacin - as other fluoroquinolines - have the potential to induce cartilage lesions in juvenile rats.
Ref: Ciprofloxacin and N-methyl-ciprofloxacin induce joint cartilage lesions in immature rats. By E Lozo et al. Teratology 1996 May;53(5):32A.

The phototoxic potential of eight fluoroquinolones (norfloxacin, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, tosufloxacin, sparfloxacin and gatifloxacin) was evaluated by using three in vitro methods of cytotoxicity against mammalian cells, erythrocyte lysis and DNA strand breakage. All fluoroquinolones tested with the exception of gatifloxacin, an 8-methoxy quinolone, showed DNA strand breaking activities under UV-A irradiation. Their cytotoxicity against HeLa cells was also enhanced by UV-A irradiation. In particular, the phototoxic potential of sparfloxacin, enoxacin and lomefloxacin was high in both methods. Ofloxacin is very photocytotoxic against HeLa cells, while it has low potential to cause DNA strand breakage. Norfloxacin, ciprofloxacin and enoxacin were very photohemolytic, but sparfloxacin was not, indicating that the in vivo phototoxic potencies of fluoroquinolones might not be predictable by the photohemolysis study. Gatifloxacin, a non-phototoxic quinolone, showed no phototoxic potential in any of these three in vitro tests. These results suggest that determination of DNA strand breaking activity, combined with cytotoxicity against mammalian cells, is available to predict the phototoxic potential of fluoroquinolones without laboratory animals.
Ref: In vitro method for prediction of the phototoxic potentials of fluoroquinolones; by T. Yamamoto et al. Toxicology in Vitro - Volume 15, Issue 6 , December 2001, Pages 721-727.

In the last few years, a marked decrease in male fertility has been reported. Environmental factors were recently suspected for this effect. Among those factors is the misuse of drugs and in particular antibiotics. Quinolones are a group of antibacterial agents with broad-spectrum activity. Testicular impairment of some quinolone members is controversial; a matter which stimulated our attention to investigate the adverse testicular effects of the most familiar quinolone members, namely: ofloxacin, ciprofloxacin and pefloxacin. They were given to rats in doses of 72, 135 and 72 mg kg-1day-1p.o., respectively, for 15 consecutive days. Ofloxacin was also used to establish a dose–response relationship in doses of 36, 72 and 360 mg kg-1day-1p.o. for 15 consecutive days. Results revealed that ofloxacin, ciprofloxacin and pefloxacin reduced testicular LDH-X activity by 39.8%, 62.7% and 60.7%, respectively. Moreover, sperm count, motility and daily sperm production were markedly decreased. Ofloxacin induced a dose-dependent decrease in testicular LDH-X activity, sperm count and motility. Furthermore, daily sperm production showed a marked reduction which amounted to 26.1% and 40.0% following administration of ofloxacin (72, 360 mg kg-1day-1*15 days), respectively. Moreover, administration of ofloxacin resulted in marked testicular histopathological changes. It is concluded that, ofloxacin, ciprofloxacin and pefloxacin significantly impaired both testicular function and structure in rats.
Ref: ADVERSE TESTICULAR EFFECTS OF SOME QUINOLONE MEMBERS IN RATS; by ADEL R. A. ABD-ALLAH et al. Pharmacological Research Volume 41, Issue 2 , February 2000, Pages 211-219.

BACKGROUND: The objective of the present study was to test and compare the effect of floroquinolones on fracture healing as assessed histopathologically. METHODS: A total of twenty five Wistar rats were arbitrarily assigned to five groups with five animals each. Bilateral closed femoral fracture was constructed manually in all groups. The first group did not receive any drug as control (C). The 2nd, 3rd, 4th, and the last group were treated with norfloxacin (N), ofloxacin (O), pefloxacin (P) and ciprofloxacin (Ci) respectively. Antibiotic administration was started on the 7th day after the fracture incident. All the treatments were discontinued twenty days after the incident all the rats were sacrificed , and the fracture calluses together with affected femurs were resected en bloc at the fourth week after fracture. RESULTS: Average healing grades of control group was higher than all the other antibiotic groups. Mean healing grades of control ( 5 ; n:8), ofloxacin (4.1; n:7), ciprofloxacin (3.9; n:8), norfloxacin (3.4 ; n:9) and pefloxacin groups (2.6 ; n:10) were recorded.. Statistically significant differences between antibiotherapy groups ( excluding. norfloxacin) and the control group were detected. CONCLUSIONS: The current histopathological study has shown that all the studied floroquinolones retarded fracture healing in rats.
Ref: A Comparison of effects of floroquinolones on fracture healing (An experimental study in rats). By Tuncay I, Ozbek H, Kosem M, Unal O. Ulus Travma Derg. 2005 Jan;11(1):17-22.

Name: Clinafloxacin
CAS No. 105956-97-6
Formula: C17-H17-Cl-F-N3-O3
Structure:  
Other Names:

PD 127321

Class Fluoroquinolone
Effects
(some, not all)
• Photoclastogenic
Photogenotoxic 
• Phototoxic
 
Hypoglycaemia
Use(s):

Antiinfective agent

Clinafloxacin Abstracts:

... Phototoxicity has been described for all quinolones, but derivatives with a halogen atom at position 8 show the highest potential for such reactions (e.g. clinafloxacin)...
Ref: Clinical toxicological aspects of fluoroquinolones; by Ralf Stahlmann. Toxicology Letters - Volume 127, Issues 1-3 , 28 February 2002, Pages 269-277.

The photochemical clastogenic potential of 12 quinolone antibacterial agents with or without light irradiation was assessed by an in vitro chromosomal aberration test using cultured CHL cells. Exposure to all test compounds, except for DK-507k, increased the incidence of cells with structural aberrations excluding gap (TA) following light irradiation. Test compounds used in the present study under light irradiation were divided into three groups based on their ED50 values, doses inducing chromosomal aberrations in 50% of cells. The first group with ED50 values below 30 g/ml includes sparfloxacin (SPFX), clinafloxacin (CLFX), gemifloxacin (GMFX), lomefloxacin (LFLX), sitafloxacin (STFX), grepafloxacin (GPFX) and fleroxacin (FLRX); the second group with ED50 values of 100 g/ml, enoxacin (ENX) and levofloxacin (LVFX); the third group with little or no potency, moxifloxacin (MFLX), trovafloxacin (TVFX) and DK-507k. The photochemical clastogenicity of these compounds correlates well with their reported in vivo phototoxic potentials. In the chemical structure and clastogenicity relationships, substitution of a methoxy group at the C-8 position in the quinolone nucleus was confirmed to reduce not only photochemical clastogenicity, but also the clastogenic potential of quinolone antibacterial agents.
Ref: In vitro photochemical clastogenicity of quinolone antibacterial agents studied by a chromosomal aberration test with light irradiation. By Satoru Itoh et al. Mutation Research/Genetic Toxicology and Environmental Mutagenesis Volume 517, Issues 1-2 , 27 May 2002, Pages 113-121.

Fluoroquinolone antiinfective drugs exhibit phototoxic, photogenotoxic, and photocarcinogenic activities in experimental systems which may be interrelated. Clinafloxacin (CLX), a new fluoroquinolone, is a potent antiinfective agent being developed for use in life-threatening infections. While this drug has previously been demonstrated to be phototoxic, this report evaluated the photogenotoxic and photocarcinogenic potential of CLX. When Skh-1 mice were administered CLX in the presence of ultraviolet light (UVA) at the maximum tolerated dose expected for a photocarcinogenicity bioassay, induction of DNA strand breakage was noted in keratinocytes isolated from these animals. When compared with other well-studied fluoroquinolonesin vitro,CLX and Lomefloxacin (LMX) were equally effective in producing chromosome damage and DNA strand breakage in Chinese hamster ovary (CHO) cells exposed to UVA. Treatment of CHO cells with CLX in the presence of UVA also resulted in hydroxyl radical formation. However, coincubation of CHO cells with CLX and various antioxidants markedly reduced hydroxyl radical formation, but inhibited photogenotoxicity only to a limited extent. Thus, while reactive oxygen species contribute to the photogenotoxic activity of CLX, other factors may be involved. Since CLX exhibits both phototoxic and photogenotoxic activity, we predict that CLX would be photocarcinogenic in vivo.The present study suggests that under conditions of human exposure, the potential risk for CLX-induced photocarcinogenicity is small.
Ref: In VitroPhotogenotoxic Activity of Clinafloxacin: A Paradigm Predicting Photocarcinogenicity; by S. J. Bulera1, J. C. Theiss, T. A. Festerling and F. A. de la Iglesia. Toxicology and Applied Pharmacology Volume 156, Issue 3 , 1 May 1999, Pages 222-230.

The new fluoroquinolones (clinafloxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, moxifloxacin, sitafloxacin, sparfloxacin and trovafloxacin) offer excellent activity against Gram-negative bacilli and improved Gram-positive activity (e.g. against Streptococcus pneumoniae and Staphylococcus aureus) over ciprofloxacin... Several of these agents have either been withdrawn from the market, had their use severely restricted because of adverse effects (clinafloxacin because of phototoxicity and hypoglycaemia; grepafloxacin because of prolongation of the QTc and resultant torsades de pointes; sparfloxacin because of phototoxicity; and trovafloxacin because of hepatotoxicity), or were discontinued during developmental phases. The remaining fluoroquinolones such as gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin have adverse effect profiles similar to ciprofloxacin. Extensive post-marketing safety surveillance data (as are available with ciprofloxacin and levofloxacin) are required for all new fluoroquinolones before safety can be definitively established. Drug interactions are limited; however, all fluoroquinolones interact with metal ion containing drugs (eg. antacids)..
Ref: A critical review of the fluoroquinolones: focus on respiratory infections; by GG Zhanel et al. Drugs. 2002;62(1):13-59.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11790155

Name: Enoxacin
CAS No.  74011-58-8
Formula: C15-H17-F-N4-O3
Structure:  
Other Names:

AT-2266
BRN 3628995
Bactidan
CCRIS 5242
CI 919
Comprecin
Enoram
Flumark
PD 107779
Penetrex

Class Fluoroquinolone
Effects
(some, not all)
• Photogenotoxic
Photoclastogenic
Photohemolytic

• Phototoxic 
Use: An orally administered broad-spectrum fluoroquinolone antibacterial agent active against most gram-negative and gram-positive bacteria. Its clinical efficacy has been confirmed in a variety of systemic infections and particularly in urinary tract infections. The drug is well tolerated by adults, but should not be used in children and pregnant women.

Enoxacin Abstracts:

The phototoxic potential of eight fluoroquinolones (norfloxacin, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, tosufloxacin, sparfloxacin and gatifloxacin) was evaluated by using three in vitro methods of cytotoxicity against mammalian cells, erythrocyte lysis and DNA strand breakage. All fluoroquinolones tested with the exception of gatifloxacin, an 8-methoxy quinolone, showed DNA strand breaking activities under UV-A irradiation. Their cytotoxicity against HeLa cells was also enhanced by UV-A irradiation. In particular, the phototoxic potential of sparfloxacin, enoxacin and lomefloxacin was high in both methods. Ofloxacin is very photocytotoxic against HeLa cells, while it has low potential to cause DNA strand breakage. Norfloxacin, ciprofloxacin and enoxacin were very photohemolytic, but sparfloxacin was not, indicating that the in vivo phototoxic potencies of fluoroquinolones might not be predictable by the photohemolysis study. Gatifloxacin, a non-phototoxic quinolone, showed no phototoxic potential in any of these three in vitro tests. These results suggest that determination of DNA strand breaking activity, combined with cytotoxicity against mammalian cells, is available to predict the phototoxic potential of fluoroquinolones without laboratory animals.
Ref: In vitro method for prediction of the phototoxic potentials of fluoroquinolones; by T. Yamamoto et al. Toxicology in Vitro - Volume 15, Issue 6 , December 2001, Pages 721-727.

The photochemical clastogenic potential of 12 quinolone antibacterial agents with or without light irradiation was assessed by an in vitro chromosomal aberration test using cultured CHL cells. Exposure to all test compounds, except for DK-507k, increased the incidence of cells with structural aberrations excluding gap (TA) following light irradiation. Test compounds used in the present study under light irradiation were divided into three groups based on their ED50 values, doses inducing chromosomal aberrations in 50% of cells. The first group with ED50 values below 30 g/ml includes sparfloxacin (SPFX), clinafloxacin (CLFX), gemifloxacin (GMFX), lomefloxacin (LFLX), sitafloxacin (STFX), grepafloxacin (GPFX) and fleroxacin (FLRX); the second group with ED50 values of 100 g/ml, enoxacin (ENX) and levofloxacin (LVFX); the third group with little or no potency, moxifloxacin (MFLX), trovafloxacin (TVFX) and DK-507k. The photochemical clastogenicity of these compounds correlates well with their reported in vivo phototoxic potentials. In the chemical structure and clastogenicity relationships, substitution of a methoxy group at the C-8 position in the quinolone nucleus was confirmed to reduce not only photochemical clastogenicity, but also the clastogenic potential of quinolone antibacterial agents.
Ref: In vitro photochemical clastogenicity of quinolone antibacterial agents studied by a chromosomal aberration test with light irradiation. By Satoru Itoh et al. Mutation Research/Genetic Toxicology and Environmental Mutagenesis Volume 517, Issues 1-2 , 27 May 2002, Pages 113-121.

Name: Fleroxacin
CAS No.  79660-72-3 
Formula: C17-H18-F3-N3-O3
Structure:  
Other Names: AM 833
BRN 4300996
CCRIS 3972
Megalone
Ro 23-6240
Ro 23-6240/000
Class Fluoroquinolone
Effects
(some, not all)
• Photocarcinogenic 
• Photoclastogenic
• Phototoxic 
Use:

Anti-infective agents, fluoroquinolone
Antibacterial
Drug / Therapeutic Agent

6,8-Difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid. A third-generation fluoroquinolone derivative with a broad antimicrobial spectrum. The drug strongly inhibits the DNA-supercoiling activity of DNA gyrase which may account for its antibacterial activity.

Fleroxacin Abstracts:

... Fluoroquinolones (FQ) are a relatively new class of antibacterials that are useful in the treatment of gram-negative bacterial infections. When used in humans FQ's often cause phototoxicity. Recent studies have shown that lomefloxacin and fleroxacin cause squamous cell carcinomas in hairless mice injected with these drugs and irradiated with UV-A (315-400) nm. We have studied the photochemical properties of lomefloxacin and related FQ's to determine why these drugs as a class are phototoxic and why lomefloxacin and fleroxacin are photocarcinogenic. Singlet oxygen (1O2) and superoxide yields for the FQ antimicrobials do not correlate with their phototoxic potentials. However, photocleavage of pBR322 DNA by the FQ antibiotics is at least 10-fold more efficient for difluorinated quinolones (lomefloxcin and fleroxacin) than for monofluorinated analogs. 1O2 does not induce photocleavage. Futhermore, the inhibitory effect of O2 on the induction of frank strand breaks makes it unlikely that superoxide could play a major role in the photocleavage of DNA by these antibiotics. We have now found that upon UVA-irradiation the F-8 fluorine atoms of lomefloxacin and fleroxacin are lost as fluoride with the concomitant generation of a carbene at C-8. In contrast non-photocarcinogenic FLQ's norfloxacin and ciprofloxacin did not exhibit UVA-induced fluoride loss...
Ref:
MECHANISMS OF CHEMICALLY INDUCED PHOTOSENSITIVITY by CF CHIGNELL.
1997 - Crisp Data Base National Institutes of Health. Document Number: CRISP/98/ES50046-19.

The photochemical clastogenic potential of 12 quinolone antibacterial agents with or without light irradiation was assessed by an in vitro chromosomal aberration test using cultured CHL cells. Exposure to all test compounds, except for DK-507k, increased the incidence of cells with structural aberrations excluding gap (TA) following light irradiation. Test compounds used in the present study under light irradiation were divided into three groups based on their ED50 values, doses inducing chromosomal aberrations in 50% of cells. The first group with ED50 values below 30 g/ml includes sparfloxacin (SPFX), clinafloxacin (CLFX), gemifloxacin (GMFX), lomefloxacin (LFLX), sitafloxacin (STFX), grepafloxacin (GPFX) and fleroxacin (FLRX); the second group with ED50 values of 100 g/ml, enoxacin (ENX) and levofloxacin (LVFX); the third group with little or no potency, moxifloxacin (MFLX), trovafloxacin (TVFX) and DK-507k. The photochemical clastogenicity of these compounds correlates well with their reported in vivo phototoxic potentials. In the chemical structure and clastogenicity relationships, substitution of a methoxy group at the C-8 position in the quinolone nucleus was confirmed to reduce not only photochemical clastogenicity, but also the clastogenic potential of quinolone antibacterial agents.
Ref: In vitro photochemical clastogenicity of quinolone antibacterial agents studied by a chromosomal aberration test with light irradiation. By Satoru Itoh et al. Mutation Research/Genetic Toxicology and Environmental Mutagenesis Volume 517, Issues 1-2 , 27 May 2002, Pages 113-121.

 
Fluoride Action Network | Pesticide Project | 315-379-9200 | pesticides@fluoridealert.org