Collection and Separation of Fleroxacin and Ciprofloxacin in Ultrasound-Assisted Ionic Liquid Salting-Out Microextraction System.

An ultrasound-assisted ionic liquid (IL) salting-out microextraction system was developed and applied for the extraction of quinolone antibiotics from urine. A precipitate was formed from the salt and IL, and it acted as the sorbent for the analytes. The precipitate containing the analyte was separated by filtration, redissolved, and the solution then was evaporated. The resulting extract was redissolved for high-performance liquid chromatographic analysis. Several parameters, including type and volume of IL, the type and amount of salts, sample pH, temperature and extraction time were optimized. Under the optimal experimental conditions, the limits of detection for fleroxacin and ciprofloxacin were 3.12 and 4.97 µg L-1, respectively. When the present method was applied to real urine sample analysis, the analyte recoveries ranged from 82.3 to 106.8%. This ultrasound-assisted IL salting-out microextraction system had the characteristics of high recoveries, shorter separation time and easy-to-perform collection procedure, which yielded the method to have potential for wide application.

A highly sensitive and selective "turn-on" fluorescent probe for detection of fleroxacin in human serum and urine based on a lanthanide functionalized metal-organic framework.

Cation exchange, a facile and non-destructive post-synthetic modification method, is applied to [(Me)4N]2[Pb6K6(m-BDC)9(OH)2]·H2O (1) (1,3-H2BDC = 1,3-benzenedicarboxylic acid) to prepare a series of lanthanide functionalized metal-organic frameworks. The fluorescence properties of Ln3+@1 (Ln = Eu, Tb, Sm and Dy) are investigated. The results demonstrate that the framework of 1 is capable of sensitizing both Eu3+ and Tb3+ ions effectively. Remarkably, the rapid and stable fluorescence sensitization of Eu3+@1 can be observed in the presence of fleroxacin in aqueous solution, indicating that the hybrid system can be designed as a highly sensitive and selective probe for fleroxacin. As a novel "turn-on" fluorescent probe, Eu3+@1 is regarded as a promising candidate for applications in clinical diagnosis, due to its merits of high antidisturbance, chemical stability and a low detection limit (43.91 ng mL-1). In this paper, the practical application of luminescent Eu3+@1 is highlighted, and its possible sensing mechanism is also described.

Capillary electrophoresis with electrochemiluminescence detection for simultaneous determination of proline and fleroxacin in human urine.

The content of free proline (Pro) in body fluids is a biological parameter for patients with renal insufficiency and chronic uraemia. Fleroxacin (FLX) must be used cautiously because of adverse reactions. Its dosage must be adjusted according to the degree of renal insufficiency. In a clinical setting the simultaneous determination of Pro and FLX in body fluids is necessary for the rational utilization of FLX. A capillary electrophoresis (CE) method based on electrochemiluminescence (ECL) detection with Ru(bpy)(3) (2+) was developed for the simultaneous determination of Pro and FLX in human urine. Parameters related to separation and detection were investigated and optimized. The most favourable resolution and high sensitivity were obtained using a 15 mM phosphate buffer at pH 9.6 with the detection potential at 1.15 V. Under optimized conditions, the standard curves were linear in the range of 0.1-80 microg/mL for Pro and 0.1-100 microg/mL for FLX. Detection limits(3sigma) of 0.3 ng/mL for FLX and 0.02 microg/mL for Pro were obtained. Relative standard derivations (RSDs) of the ECL intensity and the migration time were 3.2% and 0.9% for 4 microg/mL Pro and 3.7% and 1.2% for 4 microg/mL FLX, respectively. The recoveries were in the range of 94.8-99.6% for Pro with RSDs of 2.8%-3.6% and 94.7-97.8% for FLX with RSDs of 2.9%-3.7%. The proposed method was successfully applied to determine the amounts of Pro and FLX in human urine.

Influence of sex on the pharmacokinetic interaction of fleroxacin and ciprofloxacin with caffeine.

BACKGROUND: Previous pharmacokinetic studies have shown that a number of the quinolones inhibit the metabolism of caffeine. OBJECTIVE: To evaluate the effect of sex on the interaction between two quinolones and caffeine. DESIGN: Multiple-dose, double-blind, randomised, three-period crossover study. PARTICIPANTS: Twelve male and twelve female healthy volunteers. METHODS: Subjects received by mouth either fleroxacin 400 mg once daily and caffeine 100 mg three times daily, ciprofloxacin 500 mg twice daily and caffeine 100 mg three times daily, or caffeine alone, for 3 days. Subjects received each of the other regimens after 12-day washout periods. Plasma and urine concentrations were determined by validated high-performance liquid chromatography procedures and the data were analysed by noncompartmental linear pharmacokinetic methods. RESULTS: Analysis of the interaction by sex revealed that females showed a significant difference in caffeine pharmacokinetics in the presence of ciprofloxacin (area under the concentration-time curve [AUC], peak plasma concentration [C(max)], time to C(max) [t(max)] and apparent total body clearance [CL/F]) and fleroxacin (AUC and CL/F) when compared with males. Significant differences between sexes were also observed in the pharmacokinetics of ciprofloxacin (AUC, elimination rate constant [beta] and CL/F) and fleroxacin (C(max) and beta) in the presence of caffeine. However, these significant differences disappeared when AUC and C(max) were normalised to 70 kg bodyweight and CL/F was expressed as per kg bodyweight. CONCLUSION: The effect of quinolones on the pharmacokinetics of caffeine, and the reciprocal effect, are different between the sexes, due in part to different bodyweights.

Voltammetric analysis of certain 4-quinolones in pharmaceuticals and biological fluids.

The voltammetric behaviour of Enrofloxacin (I), Sparfloxacin (II) and Fleroxacin (III) was studied using direct current (DCt), differential pulse (DPP) and alternating current (ACt). All the drugs manifest cathodic waves in Britton Robinson buffer over the pH range of 4.0-11.98. The waves were characterized as being irreversible, diffusion-controlled with limited adsorption properties. The diffusion current concentration relationships were found to be rectilinear over the ranges 4 x 10(-5) x 10(-4) M, 1 x 10(-5)-2 x 10(-4) M, 1 x 10(-5)-4 x 10(-4) M using DCt mode for I, II and III, respectively and 1 x 10(-6)-4 x 10(-5) M, 1 x 10(-6)-1 x 10(-4) M, and 2 x 10(-6)-8 x 10(-5) M, using DPP mode for I, II and III respectively, with minimum detectability (S/N = 3) of 1 x 10(-7) M for I, II and 2 x 10(-7) M for III. The proposed method was successfully applied to the determination of the studied compounds either per se or in formulations and biological fluids. The results obtained were concordant to those given using reference methods.

Single-dose pharmacokinetic study of ciprofloxacin and fleroxacin in healthy adult Nigerian volunteers.

The kinetics of absorption, distribution and elimination of ciprofloxacin and fleroxacin (following an intravenous dose of 200 mg), were evaluated in 24 adult healthy male Nigerian volunteers. Appropriate mathematical models were applied with the aid of a microcomputer software program for the estimation of the basic pharmacokinetic parameters. Appropriate statistical tests and profiles formed the basis for accepting or rejecting a proposed model. For parametric comparisons between the profile of the two drugs, the null hypothesis of no difference in their pharmacokinetic profile was proposed. All statistical tests were performed at a significance level of 95% (alpha = 0.05) and the 95% confidence level was determined where appropriate. Additionally, the model-independent or stochastic method of analysis was also employed in the pharmacokinetic evaluation of the blood level data. The parametric estimates obtained from both methods were compared. The plasma elimination half-life (t1/2) was estimated as 13.8 +/- 5.5 h for fleroxacin and 7.5 +/- 4.0 h for ciprofloxacin; the maximal plasma concentration (Cmax) was 0.8 +/- 0.3 and 2.3 +/- 1.0 mg/l for fleroxacin and ciprofloxacin, respectively, whilst the volume of distribution (Vd) was 2.5 +/- 1.6 and 0.4 +/- 0.3 liters/kg for fleroxacin and ciprofloxacin, respectively. 71 and 70% of unchanged drug were excreted in urine for fleroxacin and ciprofloxacin, respectively. With respect to comparative values, the results confirmed trends already observed in the literature, particularly as regards the t1/2. However, for fleroxacin there was a significant deviation from the literature trends with respect to Vd, Cmax and AUC. The results also confirmed earlier findings, advocating a once-daily dosage schedule for fleroxacin also in the Negroid population.

Urinary excretion and bactericidal activities of a single oral dose of 400 milligrams of fleroxacin versus a single oral dose of 800 milligrams of pefloxacin in healthy volunteers.

Twelve healthy volunteers participated in this randomized crossover study to compare the concentrations and recovery levels of fleroxacin and pefloxacin in urine and to assess their bactericidal activities against 12 strains of urinary pathogens with different susceptibilities over a wide range of MICs. The volunteers received a single oral dose of 400 mg of fleroxacin or 800 mg of pefloxacin. The mean cumulative renal excretion of unchanged fleroxacin, N-demethyl-fleroxacin, and N-oxide-fleroxacin accounted for 67, 7, and 6% of the total dose, respectively. The total urinary recovery of pefloxacin and the active metabolite norfloxacin was 34%. In the time-kill and the urinary bactericidal titer (UBT) studies, only the subjects' urine not supplemented with broth was used. With most tested organisms and both quinolones it took more than 8 h to achieve a reduction in CFU of 99.9% (3 log units). Overall, there was a good correlation between UBTs and MICs for the strains. Against Escherichia coli ATCC 25922 the median UBTs were similar for both antibiotics and at least 1:8 for 96 h; against the E. coli strain for which the MIC was 0.5 microgram/ml the UBT was at least 1:4 for 48 h. The UBTs of both drugs against Klebsiella pneumoniae were at least 1:16 for 72 h. The UBTs for Staphylococcus aureus (the MIC for which was 16 micrograms/ml) of both antibiotics were low, and in some of the samples, no bactericidal titers were observed. UBTs for Proteus mirabilis of pefloxacin are significantly higher than those of fleroxacin. For Pseudomonas aeruginosa the median UBTs were present for the 24-to-48-h interval. The same is true for Enterococcus faecalis. Against Staphylococcus saprophyticus, UBTs were present for at least 48 h with both quinolones. Overall, a single oral dose of 400 mg of fleroxacin exhibits UBTs comparable to those of 800 mg of pefloxacin. Therefore, it may be expected that half of the dose of fleroxacin gives comparable results in the treatment of urinary tract infections; this should be substantiated in comparative clinical trials.

Penetration of fleroxacin into breast milk and pharmacokinetics in lactating women.

Fleroxacin was administered to seven lactating women as a single oral dose of 400 mg. Plasma, urine, and milk samples were collected for up to 48 h after administration. Drug concentrations were determined by a reversed-phase high-pressure liquid chromatography method and were used for the pharmacokinetic evaluation. At approximately 2 h after oral administration, a maximum concentration of 5.6 mg/liter was determined in plasma; the area under the plasma concentration-time curve (AUC) amounted to 70.3 mg.h/liter, and the elimination half-life in the postdistributive phase was 8 h. Total systemic clearance was 97.3 ml/min, and urinary excretion was 38% of the dose within 48 h. In addition, 8.6% of the N-demethyl metabolite and 4.4% of the N-oxide metabolite were recovered from urine. In comparison with previous results obtained with healthy male volunteers, the time to reach maximum concentrations in plasma was twice as long in the nursing women, and total clearance as well as urinary elimination were reduced by 25%. In breast milk, the mean maximum concentration was 3.5 mg/liter, which was reached 2.6 h after drug administration. The elimination half-life of fleroxacin in milk was identical to that in plasma, and the AUC reached 43.3 mg.h/liter. On the basis of the comparison of the AUC in milk versus the AUC in plasma, the proportion of fleroxacin penetration into milk was 62%. The cumulative excretion in milk amounted to only 0.219 mg within 48 h. On the basis of an average daily intake of milk of a breast-fed child of 150 ml/kg of body weight, the maximum daily ingested fleroxacin dose would not exceed 10 mg. However, quinolones are known to induce arthropathy in juvenile animals, and therefore, administration of fleroxacin to breast-feeding women cannot be allowed.

Fleroxacin pharmacokinetics in patients with liver cirrhosis.

In this open-label study, the disposition of fleroxacin in liver disease in 12 healthy male volunteers, 6 male cirrhotics without ascites (group A), and 6 male cirrhotics with ascites (group B) was evaluated. Fleroxacin (400 mg) was administered orally and intravenously to each subject in a random crossover fashion. Fleroxacin was completely absorbed and achieved similar peak concentrations in plasma in all three study groups (P greater than 0.05). The volume of distribution exceeded 1 liter/kg in healthy controls and was not affected by liver impairment (P greater than 0.05). Only group B demonstrated differences in the pharmacokinetic parameters evaluated: the systemic and renal clearances of fleroxacin and the renal clearances and clearances of the two major metabolites of fleroxacin formed, N-demethyl fleroxacin and fleroxacin N-oxide, were significantly lower and the half-lives of the parent drug and its metabolites were significantly longer in group B than in healthy controls and group A (P less than 0.05). The elimination of the two metabolites appeared to be formation rate limited in all three study groups. It was concluded from this study that a 50% reduction in the fleroxacin maintenance dose in patients with liver disease appears justified only in patients with ascites. However, no change in the fleroxacin loading dose is needed in patients with compromised liver function.