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Flumequine

Clinical data
Other names	9-Fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo-quinolizine-2-carboxylic acid
AHFS/Drugs.com	International Drug Names
ATC code	J01MB07 (WHO)
Legal status
Legal status	removed from clinical use
Pharmacokinetic data
Excretion	urine and feces
Identifiers
IUPAC name 7-fluoro-12-methyl-4-oxo-1-azatricyclotrideca-2,5,7,9(13)-tetraene-3-carboxylic acid
CAS Number	42835-25-6
PubChem CID	3374
UNII	UVG8VSP2SJ
KEGG	D02302
CompTox Dashboard (EPA)	DTXSID5045623
ECHA InfoCard	100.050.857
Chemical and physical data
Formula	C14H12FNO3
Molar mass	261.25 g/mol g·mol
Melting point	253 to 255 °C (487 to 491 °F)
(verify)

Flumequine is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class used to treat bacterial infections. It is a first-generation fluoroquinolone antibacterial that has been removed from clinical use and is no longer being marketed. It kills bacteria by interfering with the enzymes that cause DNA to unwind and duplicate. Flumequine was used in veterinarian medicine for the treatment of enteric infections (all infections of the intestinal tract), as well as to treat cattle, swine, chickens, and fish, but only in a limited number of countries. It was occasionally used in France (and a few other European Countries) to treat urinary tract infections under the trade name Apurone. However this was a limited indication because only minimal serum levels were achieved.

History

The first quinolone used was nalidixic acid (was marketed in many countries as Negram) followed by the fluoroquinolone flumequine. The first-generation fluoroquinolone agents, such as flumequine, had poor distribution into the body tissues and limited activity. As such they were used mainly for treatment of urinary tract infections. Flumequine (benzo quinolizine) was first patented in 1973, (German Patent) by Rikker Labs. Flumequine is a known antimicrobial compound described and claimed in U.S. Pat. No. 3,896,131 (Example 3), July 22, 1975. Flumequine is the first quinolone compound with a fluorine atom at the C6-position of the related quinolone basic molecular structure. Even though this was the first fluoroquinolone, it is often times overlooked when classifying the drugs within this class by generations and excluded from such a list.

Though used frequently to treat farm animals and on occasion household pets, flumequine was also used to treat urinary tract infections in humans. Flumequine, was used transiently treat urinary infections until ocular toxicity was reported. as well as liver damage and anaphylactic shock.

In 2008, the United States Food and Drug Administration (FDA) requested that all quinolone/fluoroquinolone drugs package inserts include a Black Boxed Warning concerning the risk of spontaneous tendon ruptures, which would have included flumequine. The FDA also requested that the manufacturers send out Dear Doctor Letters regarding this new warning. Such tendon problems have also been associated with flumequine.

Drug residue

The use of flumequine in food animals had sparked considerable debate. Significant and harmful residues of quinolones have been found in animals treated with quinolones and later slaughtered and sold as food products. There has been significant concern regarding the amount of flumequine residue found within food animals such as fish, poultry and cattle. In 2003 the Joint FAO/WHO Committee on Food Additives (JECFA) withdrew the maximum residue limits (MRLs) for flumequine and carbadox based on evidence showing both are direct acting genotoxic carcinogens, therefore the Committee was unable to establish an Acceptable Daily Intake (ADI) for human exposure to such residues. The role of JECFA is to evaluate toxicology, residue chemistry and related information and make recommendations for acceptable daily intake (ADI) levels and maximum residue limits (MRLs). At its 16th session, held May 2006, the Committee on Residues of Veterinary Drugs in Foods (CCRVDF) requested information on registered uses of flumequine. As the CCRVDF did not receive any information regarding the registered uses of flumequine that they had requested, the committee members agreed to discontinue work on the MRLs for flumequine in shrimp.

Licensed uses

Urinary tract infections (veterinary and human)

Availability

Veterinary use:

• Solution; Oral; 20% (prescription only)
• Solution; Oral; 10% (prescription only)

Human use:

• Tablet; Oral; Flumequine 400 mg (discontinued)

Mode of action

Ciprofloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV, enzymes necessary to separate bacterial DNA, thereby inhibiting cell division.

This mechanism can also affect mammalian cell replication. In particular, some congeners of this drug family (for example those that contain the C-8 fluorine), display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models.

Although quinolones are highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone induced DNA damage was first reported in 1986 (Hussy et al.).

Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micronuclei.

As such, some fluoroquinolones may cause injury to the chromosome of eukaryotic cells.

There continues to be considerable debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe adverse reactions experienced by some patients following fluoroquinolone therapy.

Adverse reactions

Flumequine was associated with severe ocular toxicity, which precluded its use in human patients. Drug-induced calculi (kidney stones) has been associated with such therapy as well. Anaphylactic shock induced by flumequine therapy has also been associated with its use. Anaphylactoid reactions such as shock, urticaria, and Quincke’s oedema have been reported to generally appear within two hours after taking the first tablet. There were eighteen reports listed within the WHO file in 1996. As with all drugs within this class, flumequine therapy may result in severe central nervous system (CNS) reactions, phototoxicity resulting in skin reactions like erythema, pruritus, urticaria and severe rashes, gastrointestinal and neurological disorders.

History of the black box warnings

Musculoskeletal disorders attributed to use of quinolone antibiotics were first reported in the medical literature in 1972, as an adverse reaction to nalidixic acid. Rheumatic disease after use of a fluoroquinolone (norfloxacin) was first reported eleven years later. In response to a 1995 letter published in the New England Journal of Medicine, representatives of the U.S. Food and Drug Administration (FDA) stated that the agency would "update the labeling for all marketed fluoroquinolones to include a warning about the possibility of tendon rupture."

By August 1996, the FDA had not taken action, and the consumer advocacy group Public Citizen filed a petition with the FDA, prompting the agency to act. Two months later, the FDA published an alert in the FDA Medical Bulletin and requested that fluoroquinolone package inserts be amended to include information on this risk.

Nine years later, in 2005, the Illinois Attorney General filed a second petition with the FDA, again seeking Black Box Warnings and "Dear Doctor" letters emphasizing the risk of tendon rupture; the FDA responded that it had not yet been able to reach a decision on the matter. In 2006, Public Citizen, supported by the Illinois Attorney General, renewed its demand of ten years prior for Black Box Warnings by filing a third petition requesting such changes be made. When the FDA failed to respond to these two petitions as required by law Public Citizen, in January 2008, filed suit to compel the FDA to respond to their 2006 petition. On July 7, 2008 the FDA requested that the makers of systemic-use fluoroquinolones add a boxed warning regarding spontaneous tendon ruptures, and to develop a Medication Guide for patients. The package inserts for Ciprofloxacin, Avelox (moxifloxacin), Proquin XR, Factive (gemifloxacin), Floxin (ofloxacin), Noroxin (norfloxacin) and Levaquin (levofloxacin) were amended on September 8, 2008 to include these new warnings. Bayer, which manufactures Cipro, Avelox and Proquin XR, issued a Dear Healthcare Professional letter on October 22 concerning these changes. Ortho-McNeil, the manufacturers of Levaquin, issued a similar letter in November. through the Health Care Notification Network, a registration-only website that distributes drug alerts to licensed healthcare professionals.

Review of the FDA website indicates that the majority of the generic versions of the fluoroquinolones have not been updated to include this Black Box Warning as of September 2009. In addition, there are numerous reports that claim that this information has not been dessiminated to the pharmacist, the name brand products continue to contain the previous labels that are absent of this warning, and the Medication Guide has not been made available to the pharmicist or physician for distribution.

Drug interactions

Flumequine was found to have no effect on theophylline pharmacokinetics.

Chemistry

Flumequine is a 9-fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzoquinolizine-2-carboxylic acid. The molecular formula is C14H12FNO3 It is a white powder, odorless, flavorless, insoluble in water but soluble in organic solvent.

Pharmacokinetics

Flumequine is considered to be well absorbed and is excreted in the urine and feces as the glucuronide conjugates of the parent drug and 7-hydroxyflumequine. It is eliminated within 168 hours post-dosing. However, studies concerning the calf liver showed additional unidentified residues, of which a new metabolite, ml, represented the major single metabolite 24 hours after the last dose and at all subsequent time points. The metabolite ml, which exhibited no antimicrobial activity, was present in both free and protein-bound fractions. The major residue found in the edible tissues of sheep, pigs, and chickens was parent drug together with minor amounts of the 7-hydroxy-metabolite. The only detected residue in trout was the parent drug.

See also

• Fluoroquinolone toxicity
• Fluoroquinolone

References

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• Quinolone antibiotics
• Organofluorides