フルメキン

The combined effects of various carcinogens found in food products are a concern for human health. In the present study, the effects of flumequine (FL) on the in vivo mutagenicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in the liver were investigated. Additionally, we attempted to clarify the underlying mechanisms through comprehensive gene analysis using a cDNA microarray. Male gpt delta mice were fed a diet of 0.03 % MeIQx, 0.4 % FL, or 0.03 % MeIQx + 0.4 % FL for 13 weeks. The effects of cotreatment with phenobarbital (PB) were also examined. Treatment with MeIQx alone increased gpt and Spi(-) mutant frequencies, and cotreatment with FL, but not with PB, further exacerbated these effects, despite the lack of in vivo genotoxicity in mice treated with FL alone. FL caused an increase in Cyp1a2 mRNA levels and a decrease in Ugt1b1 mRNA levels, suggesting that the enhancing effects of FL may be due in part to modification of MeIQx metabolism by FL. Moreover, FL induced an increase in hepatocyte proliferation accompanied by hepatocellular injury. Increases in the mRNA levels of genes encoding cytokines derived from Kupffer cells, such as Il1b and Tnf, and cell cycle-related genes, such as Ccnd1 and Ccne1, suggested that FL treatment increases compensatory cell proliferation. Thus, the present study clearly demonstrated the combined effects of 2 different types of carcinogens known as contaminants in foods.

EC50; Species: Microcystis aeruginosa (Blue-Green Algae) exponential growth phase, cell density 10X10+6/mL; Conditions: freshwater, static, 20 °C; Concentration: 8800 ug/L for 24 hr; Effect: physiology, decreased photosynthesis /formulation/

EC50; Species: Microcystis aeruginosa (Blue-Green Algae); Conditions: freshwater, static, 20 °C; Concentration: 1960 ug/L for 5 days (95% confidence interval: 1760-2160 ug/L); Effect: population, decreased chlorophyll A /96% purity/

EC50; Species: Microcystis aeruginosa (Blue-Green Algae) exponential growth phase, nonaxenic, 2x10+6 cells/mL; Conditions: freshwater, static, 21 °C, pH 7.9; Concentration: 159 ug/L for 7 days (95% confidence interval: 66-382 ug/L); Effect: population, increased chlorophyll A concentration />99.9% purity/

EC50; Species: Pseudokirchneriella subcapitata (Green Algae) CCALA433, cell density 3X10/mL; Conditions: freshwater, static, 20 °C; Concentration: 16000 ug/L for 24 hr; Effect: physiology, decreased photosynthesis /formulation/

For more Ecotoxicity Values (Complete) data for FLUMEQUINE (9 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), Koc values of 2750-24,500(2), indicate that flumequine is expected to have slight to no mobility in soil(SRC). The pKa of flumequine is 6.5(3), indicating that this compound will exist partially in anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of neutral flumequine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.7X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(5). The anion form of flumequine will not volatilize(SRC). Flumequine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.5X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). No biodegradation was observed for flumequine in water and sediment taken from eel and shrimp farm ponds(6). However, flumequine had degradation half-lives of 2.3-14.5 days in the same media when light was introduced(6), this indicates flumequine may be photodegraded on soil surfaces(SRC).

AQUATIC FATE: Based on a classification scheme(1), reported Koc values of 2750-24,500(2), indicate that flumequine is expected to adsorb to suspended solids and sediment(SRC). A pKa of 6.5(3) indicates flumequine will exist partially in the anion form at pH values of 5 to 9 and, therefore, volatilization of the anion from water surfaces is not expected(SRC). Volatilization of unionized flumequine from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 2.7X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). Flumequine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(4). According to a classification scheme(6), an estimated BCF of 3(SRC), from its log Kow of 1.60(7) and a regression-derived equation(5), suggests the potential for bioconcentration in aquatic organisms is low(SRC). No biodegradation was observed for flumequine in water and sediment taken from eel and shrimp farm ponds(8). However, flumequine had degradation half-lives of 2.3-14.5 days in the same media when light was introduced; this indicates flumequine is degraded abiotically(8).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), flumequine, which has an estimated vapor pressure of 2.5X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase flumequine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone(SRC); the half-lives for these reactions in air are estimated to be 12 hours and 6.6 days(SRC), respectively. Particulate-phase flumequine may be removed from the air by wet and dry deposition(SRC). Flumequine contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Flumequine was not detected (detection limit 0.04-0.52 ug/kg) in 16 infant and young children powdered milk samples purchased from Spanish markets(1). Flumequine was not detected (detection limit 0.4 ug/kg) in honey samples imported into Canada(2).

IDENTIFICATION AND USE: Flumequine is a fluoroquinolone compound with antimicrobial activity against Gram-negative organisms. It is used in the treatment of enteric infections in food animals and in the treatment of bacterial infections in farmed fish. Flumequine also has limited use in humans for the treatment of urinary tract infections. HUMAN EXPOSURE AND TOXICITY: Ocular side effects in 3 patients being treated with flumequine for urinary infections were reported. All 3 patients had chronic renal failure and all exhibited bilateral symmetry. Complete recovery occurred within 2 days of withdrawing the drug. ANIMAL STUDIES: Flumequine was administered by gastric tube to female mice for 14 days. No signs of alopecia or other toxicity were noted. Rats were orally administered flumequine for 14 days. Marked alopecia was observed in both sexes after 3 to 5 days treatment, which persisted for the duration of the study. In other study rats were orally administered flumequine for 14 days. Clinical signs included bloating, cyanosis, dehydration, reduced weight gain, and shedding. Guinea pigs were given oral doses of flumequine for 14 days. Mortality was noted. Beagle dogs were given daily oral doses of flumequine. All dogs survived the one-year treatment period. A decrease in food consumption was noted in all treatment groups throughout the study. A dose-dependent incidence of convulsive episodes was observed in treated dogs. The convulsions were relatively severe, of short duration (15-30 seconds), and almost always followed by ataxia and tremors. Normal behavior returned within about ten minutes after treatment. Other drug-related clinical signs observed included ataxia, hypoactivity, tremors, emesis, decreased food consumption, and body-weight loss. In an 18-month study, flumequine was administered in the feed to mice of each sex. A slight depression in body weight occurred in the high-dose group from the sixth week to termination of the study. Incidences of liver tumors seen grossly at necropsy were dose-related and more prevalent in males than in females. The incidence of hepatic toxic changes paralleled the liver tumor incidence. Chi-square analysis of the number of tumor-bearing animals indicated significant increases for the low- and high-dose males considering all tumors and benign tumors. The number of high-dose males with both benign and malignant liver tumors was also statistically significant. In females, the only significant increases occurred in the high-dose group for numbers of animals with any type or benign only tumors. In a 13-week study designed to investigate hepatotoxic lesions and the activities of hepatic drug-metabolizing enzymes, flumequine was administered to mice. The effects observed were reduced body weight, significantly increased plasma activities of alanine and aspartate aminotransferases, alkaline phosphatase and lactic dehydrogenase, and increased liver weights. Pregnant mice were orally administered flumequine from the second to fifteenth days of gestation. Incomplete ossification, invaginated trachea, dilatation of the renal pelvis, and cleft palate were observed in fetuses. These observations were interpreted as evidence of fetotoxic, not teratogenic, responses to exposure to flumequine. Pregnant rats were dosed orally with flumequine from the sixth through fifteenth days of gestation. There was a dose-related reduction of mean body weight in the treated dams and the difference from controls was significant at 400 mg/kg bw/day. The mean fetal weights of the mid- and high-dose groups were significantly lower as compared to controls. Dose-related incomplete ossification of sternebra, vertebrae, and skull bones were also noted in fetuses. No drug-related visceral or skeletal malformations were found and there was no embryotoxic effect noted in this study. Flumequine was negative in the following genotoxicity tests: Ames test, HGPRT test, Gene Mutation Assay and the Chromosome Aberration Assay.

/AQUATIC SPECIES/ Ecotoxicity and genotoxicity of widely used veterinary antimicrobials oxytetracycline and flumequine was studied with six model organisms (Vibrio fischeri, Pseudomonas putida, Pseudokirchneriella subcapitata, Lemna minor, Daphnia magna, Escherichia coli). Overall median effective concentration (EC50) values ranged from 0.22 mg/L to 86 mg/L. Pseudomonas putida was the most sensitive organism (EC50 values for 16-hr growth inhibition were 0.22 and 0.82 mg/L for oxytetracycline and flumequine, respectively), followed by duckweed Lemna minor (7-day growth inhibition, EC50 2.1 and 3.0 mg/L) and green alga Pseudokirchneriella subcapitata (4-day growth inhibition, EC50 3.1 and 2.6 mg/L). The least sensitive organism was Daphnia magna (48-hr immobilization, lowest-observed-effect concentration [LOEC] of oxytetracycline of 400 mg/L). Oxytetracycline showed limited genotoxicity (SOS-chromotest with Escherichia coli, minimal genotoxic concentration of 500 mg/L), and flumequine was genotoxic at 0.25 mg/L. Based on the reported measured concentrations (MECs) and predicted no-effect concentrations (PNECs), oxytetracycline may be concluded to be of ecotoxicological concern (calculated risk quotient=8), whereas flumequine seems to represent lower risk.

/AQUATIC SPECIES/ Toxicity tests were performed with seven fluoroquinolone antibiotics, ciprofloxacin, lomefloxacin, ofloxacin, levofloxacin, clinafloxacin, enrofloxacin, and flumequine, on five aquatic organisms. Overall toxicity values ranged from 7.9 to 23,000 ug/L. The cyanobacterium Microcystis aeruginosa was the most sensitive organism (5-day growth and reproduction, effective concentrations [EC50s] ranging from 7.9 to 1,960 ug/L and a median of 49 ug/L), followed by duckweed (Lemna minor, 7-day reproduction, EC50 values ranged from 53 to 2,470 ug/L with a median of 106 ug/L) and the green alga Pseudokirchneriella subcapitata (3-day growth and reproduction, EC50 values ranged from 1,100 to 22,700 ug/L with a median 7,400 ug/L). Results from tests with the crustacean Daphnia magna (48-hr survival) and fathead minnow (Pimephales promelas, 7-day early life stage survival and growth) showed limited toxicity with no-observed-effect concentrations at or near 10 mg/L. Fish dry weights obtained in the ciprofloxacin, levofloxacin, and ofloxacin treatments (10 mg/L) were significantly higher than in control fish. The hazard of adverse effects occurring to the tested organisms in the environment was quantified by using hazard quotients. An estimated environmental concentration of 1 ug/L was chosen based on measured environmental concentrations previously reported in surface water; at this level, only M. aeruginosa may be at risk in surface water. However, the selective toxicity of these compounds may have implications for aquatic community structure.

/AQUATIC SPECIES/ More or less well-defined mixtures of antibiotics used in aquacultures may be distributed in the aquatic environment. Therefore, a systematic mixture ecotoxicity study was performed with the aquaculture antibiotics oxytetracycline, oxolinic acid, erythromycin, florfenicol, and flumequine. Test organisms were freshwater algae (Pseudokirchneriella subcapitata), activated sludge microorganisms, and luminescent bacteria (Vibrio fischeri). Design and statistical analysis of test results were based on isobolographic analysis. Synergistic effects were observed when combinations of erythromycin and oxytetracycline were tested on activated sludge microorganisms, and in these cases model predictions indicate independent action on the different bacterial species in the sludge. As predicted from the modes of action, concentration addition was evident when flumequine and oxolinic acid were mixed and tested on sludge bacteria. In the algae test, the combined toxicity of antibiotics could not be predicted based on knowledge of the modes of action of the individual compounds. Independent of the test species, our results gave examples of combined effects that were higher than predicted based on the assumption of concentration addition. This result underlines the need to consider the effects of mixtures of antibiotics on environmental organisms. The isobolographic method appears to be a suitable tool for this purpose, particularly for well-defined mixtures with few substances.

Flumequine was not detected in 14 influent (<0.02 ug/L) or 14 effluent (<0.01 ug/L) samples collected 2008-2009 from three wastewater treatment plants from the Spanish Mediterranean area of Valencia, Spain(1). Flumequine was detected in 3% of effluent samples collected from 90 European wastewater treatment plants at 20-25.7 ng/L; samples were collected in 2010(2). Flumequine was detected at 0.20-30 and 30-101 ug/L in effluent samples from 13 wastewater treatment plants and 10 industrial wastewater plants, respectively; plants were located along the Dutch coast of the North Sea and samples were collected from 1996 to 2005(3).

Koc values of flumequine have been reported as 2750-25,500(1). According to a classification scheme(2), this Koc range suggests that flumequine is expected to have slight to no mobility in soil. The pKa of flumequine is 6.5(3), indicating that this compound will exist partially in anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/CASE REPORTS/ Ocular side effects in 3 patients being treated with flumequine for urinary infections were reported. All 3 patients had chronic renal failure and all exhibited bilateral symmetry. Complete recovery occurred within 2 days of withdrawing the drug.

/CASE REPORTS/ The efficacy and safety of flumequine were evaluated in the treatment of 121 cases uncomplicated (65.5%) and complicated (34.5%) urinary tract infections (UTI) when given as a dose of 400 mg bd. Duration of treatment ranged from 7-15 days, with a mean of 10. Thirty days post-therapy, cure persisted in 92.3% of the patients with uncomplicated UTI and in 53.7% of those with complicated UTI. Relapse or re-infection occurred in 34.1% of the patients with complicated UTI, and in 12.2%, the infecting organism did not respond to treatment. Flumequine was generally well tolerated. In 27.3% of patients gastrointestinal, and neurological disorders and skin rashes developed which in most cases were mild. Only two patients were withdrawn from the treatment. It is concluded that flumequine, administered at 800 mg daily, is highly effective in treating uncomplicated and complicated UTI.

Flumequine was detected at 0.06-1.12 mg/kg in muscle tissue of wild fish caught in the vicinity of a Norwegian farm one day after termination of flumequine treatment(1). Flumequine was detected in fish liver, back fat, skin and bone 48 days after the end of medication at 8, 8, 36 and 571 ng/g, respectively and 16, 27, 36 and 465 ng/g 70 days after treatment(2). Flumequine was not detected in muscle tissue at either the 48 or 70 day post treatment times(2).

AEROBIC: No biodegradation was observed for flumequine in water and sediment taken from eel and shrimp farm ponds(1). Flumequine was stable to degradation when added at a concentration of 100 ug/mL to aquiculture sediments(2). As no metabolites were detected, loss was assumed to be due to leaching(2). Degradation half-lives in sediment were 60 days at 0-1 cm depth and >300 days at 5-7 cm(3). Other sediment degradation half-lives were 155 days or no degradation at all over 180 days(3).

Anti-Infective Agents, Urinary; Topoisomerase II Inhibitors

MEDICATION

MEDICATION (VET)

Preparation: J.F. Gerster, German patent 2264163; idem USA patent 3896131 (1973, 1975 both to Riker).

Condensation of 5-fluoro-2-methyltetrahydroquinoline with diethyl ethoxymethylenemalonate followed by thermal cyclization gives ethyl 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo(i,j)quinolizine-2-carboxylate, which is saponified with sodium hydroxide to give flumequine.

Veterinary Drug -> ANTIMICROBIAL_AGENT -> JECFA Functional Classes

Veterinary Drug -> ANTIMICROBIAL_AGENT -> JECFA Functional Classes

Veterinary Drug -> ANTIMICROBIAL_AGENT -> JECFA Functional Classes

Pharmaceuticals -> Animal Drugs -> Approved in Taiwan