Isolation and identification of metabolites of ofloxacin in rats, dogs and monkeys

Sudo, Kenichi; Okazaki, Osamu; Tsumura, Mitsuyoshi; Tachizawa, Haruo

doi:10.3109/00498258609043563

Cited by 29 publications

(15 citation statements)

References 6 publications

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“…The transformation of enrofloxacin by M. ramannianus, including N oxidation, N dealkylation, N acetylation, and the breakdown of the piperazine ring, is similar to the mammalian metabolism of other fluoroquinolones (3,15,20). For ciprofloxacin, the major mammalian metabolites have significantly less antibacterial activity than the parent compound (24).…”

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“…In animals, fluoroquinolones are usually attacked at the piperazine or the N-methylpiperazine ring, if either is present, or at the carboxyl group (3). For example, ofloxacin, pefloxacin, and fleroxacin may be modified by N oxidation of the methylpiperazine rings (11,16,20). Enoxacin may be metabolized in animals by N acetylation, by the removal of two ethylene carbons from the piperazine ring, and by other reactions (15).…”

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Microbiological Transformation of Enrofloxacin by the Fungus Mucor ramannianus

Parshikov¹,

Freeman

Lay

et al. 2000

Appl Environ Microbiol

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Enrofloxacin metabolism by Mucor ramannianus was investigated as a model for the biotransformation of veterinary fluoroquinolones. Cultures grown in sucrose-peptone broth were dosed with enrofloxacin. After 21 days, 22% of the enrofloxacin remained. Three metabolites were identified: enrofloxacin N-oxide (62% of the total absorbance), N-acetylciprofloxacin (8.0%), and desethylene-enrofloxacin (3.5%).Fluoroquinolones are synthetic antimicrobial agents that are active against a broad spectrum of pathogenic gram-negative bacteria as well as some gram-positive bacteria and mycoplasmas (10). Several fluoroquinolones are used in clinical medicine, and enrofloxacin and sarafloxacin have been approved in the United States for veterinary use (4). The major metabolite of enrofloxacin in animals is ciprofloxacin, produced by N deethylation of the ethylpiperazine ring (21).The persistence of veterinary fluoroquinolones and the types of metabolites that result from their microbial conversion in the environment have been little known until recent years (6, 12, 22, 23; H. G. Wetzstein, Abstr. 99th Gen. Meet. Am. Soc. Microbiol. abstr. Q-262, p. 583, 1999). Currently, there is a question as to whether the use of fluoroquinolones in poultry causes the replacement of fluoroquinolone-sensitive coliform bacteria by resistant strains (2, 13).Cultures of wood-decaying basidiomycetes, including strains found in manure, have been shown to convert enrofloxacin to CO 2 and at least 11 other metabolites (12,22). Since other pathways are likely to be used by different organisms involved in the bioconversion of fluoroquinolones in the environment, we investigated the transformation of enrofloxacin by a typical zygomycetous soil fungus.Mucor ramannianus strain R-56, which had been isolated from a mushroom collected in a forest in Arkansas (17), was maintained on agar slants (14,18). Triplicate cultures for experiments were grown in sucrose-peptone broth (17) for 2 days. Enrofloxacin [1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid], as the hydrochloride, was a gift from Bayer Corp., Shawnee, Kans. Enrofloxacin hydrochloride was dissolved in 20 mM aqueous KOH and filter sterilized; 1.0 ml was added to each flask to make a final concentration of 253 M enrofloxacin. The cultures were then incubated for an additional 21 days. Cultures without enrofloxacin and dosed, noninoculated controls were also incubated.Methylene chloride extracts of cultures and controls were analyzed by high-performance liquid chromatography (HPLC) (17), using a Phenomenex (Torrance, Calif.) Prodigy 5-m ODS-3 column (10 by 250 mm) with a water-acetic acid-methanol gradient (17). The flow rate was 2.5 ml min Ϫ1 ; metabolites were quantified by the peak areas at 280 nm.For direct exposure probe-electron ionization (DEP/EI) mass spectrometry (17), the quadrupole was scanned from m/z 50 to 650. For liquid chromatography-electrospray ionization (LC/ESI) mass spectrometry (17), a Vydac RP-18 pharmaceutical (5-m) microbore column (...

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Microbiological Transformation of Enrofloxacin by the Fungus Mucor ramannianus

Parshikov¹,

Freeman

Lay

et al. 2000

Appl Environ Microbiol

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“…The metabolic disposition of oflox acin has been studied in various animal species and humans. It is well absorbed from the intestine, is distributed rapidly in all tissues except the central nervous sys tem, at much higher concentrations than in the blood, mainly in the unchanged form, and is excreted unchanged mostly in the urine and partially in the feces via the bile [4][5][6][7], In addition, the excellent che motherapeutic efficacy of ofloxacin in mouse infection models, attributable to its high oral absorbability and tissue distribu tion, has been clarified [8].…”

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Lack of Effect of Ofloxacin on Theophylline Pharmacokinetics in Rats

Okazaki

Miyazaki²,

Tachizawa³

1987

Chemotherapy

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Effect of ofloxacin, a new quinolone antibacterial agent, on the pharmacokinetics of theophylline was studied in rats in comparison with that of enoxacin and cimetidine. Ofloxacin by pretreatment with five oral doses of 50 mg/kg did not increase serum concentrations of theophylline (5 mg/kg, i.v. single) and showed no significant effect on total body clearance, serum half-life (TV,) and AUC of theophylline, while enoxacin by the same pretreatment increased significantly serum theophylline concentrations and resulted in significant effect on all the pharmacokinetic parameters. Coadministration of ofloxacin (80 mg/kg, p.o. twice) did not induce a significant effect on the pharmacokinetic parameters of theophylline at repeated doses (50 mg/kg, i.v., twice daily for 3 days). On the contrary, coadministration of enoxacin and cimetidine at the same dose as ofloxacin remarkably increased serum concentrations of theophylline at the same repeated doses, and caused a significant decrease in clearance and an increase in T_½ and AUC. The three drugs had no influence on rat serum protein binding of theophylline. Ofloxacin exhibited a weak inhibitory effect on rat hepatic microsomal cytochrome P-450-dependent monooxygenases, whereas enoxacin and cimetidine induced a significant inhibition of the enzymes. Thus, it is concluded that ofloxacin has no significant effect on the pharmacokinetics of theophylline in rats, and that enoxacin raises serum theophylline concentrations and results in a significant effect on the theophylline pharmacokinetics by inhibition of the hepatic microsomal monooxygenases in rats.

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“…In a previous paper, we reported the stereoselective disposition of the enantiomers of OFLX in rats (13), showing that there are marked pharmacokinetic differences between the enantiomers of OFLX caused by stereoselective glucuronidation. The major metabolic pathway of OFLX in rats is glucuronidation of the carboxyl group at the C-3 position of the quinolone ring (20). However, there exist species differences in OFLX glucuronidation, as the small amount of glucuronide excreted in urine by dogs and monkeys indicates (19).…”

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Enantioselective disposition of ofloxacin in humans

Okazaki

Kojima

Hakusui

et al. 1991

Antimicrob Agents Chemother

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The enantioselective disposition of ofloxacin (OFLX) was studied in healthy subjects after oral administration of (+/-)-OFLX at a dose of 200 mg. S-(-)-OFLX and R-(+)-OFLX concentrations in serum and urine were measured separately by high-performance liquid chromatography, and various pharmacokinetic parameters were calculated from the data. The ratio of S-(-) to R-(+) enantiomer concentrations in serum showed a increase with time, with S/R ratios of 1.01 at 2 h and 1.31 at 24 h. The terminal elimination half-life of S-(-)-OFLX was 6.9 h, which was significantly greater (P less than 0.05) than that of the R-(+) enantiomer (6.3 h). S-(-)-OFLX also revealed a significantly greater area under the concentration-time curve in serum, mean residence time, and total body clearance than the R-(+) enantiomer did. The renal clearance of S-(-)-OFLX (7.14 liters/h/1.73 m2) was significantly lower than that of the R-(+) enantiomer (7.53 liters/h/1.73 m2). Although the difference in the pharmacokinetic parameters of the enantiomers was small, their disposition in humans was found to be stereoselective. The difference between the enantiomers may be explained by the difference in their renal excretion.

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Isolation and identification of metabolites of ofloxacin in rats, dogs and monkeys

Cited by 29 publications

References 6 publications

Microbiological Transformation of Enrofloxacin by the Fungus Mucor ramannianus

Microbiological Transformation of Enrofloxacin by the Fungus Mucor ramannianus

Lack of Effect of Ofloxacin on Theophylline Pharmacokinetics in Rats

Enantioselective disposition of ofloxacin in humans

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