Complexation of antibacterial quinolonic acid and cinolonic derivatives with Zn(II) and Al(III): application to their determination in human urine.

Nalidixic acid, 7-hydroxymethylnalidixic acid, oxolinic acid, pipemidic acid and cinoxacine form complexes with zinc(II) in the presence of acetate buffer of pH 5.5 and oxolinic acid, pipemidic acid and cinoxacine form complexes with aluminium(III) in the presence of chloroacetate buffer of pH 3.0. In all cases, an enhancement of the fluorescence emission was observed. Fluorimetric studies on the spectral characteristics of the complexes were performed. A 1:1 stoichiometry for all the complexes was established. The association constants were calculated, by using the changes in the fluorescence of all antibacterials, that occurred when the complexes were formed. The fluorescence reactions were used to develop methods for the determination of all of the above compounds, showing a higher sensitivity than in the absence of the cationic ions. The methods were satisfactorily applied to the determination of these compounds in urine.

Determination of the chemotherapeutic quinolonic and cinolonic derivatives in urine by high-performance liquid chromatography with ultraviolet and fluorescence detection in series.

An HPLC method with ultraviolet and fluorimetric detection has been established for the separation and determination of six quinolonic and cinolonic antibiotics. A Nova-Pak C18 column (150 x 3.9 mm) and a Waters 486 UV and a Waters 470 fluorescence detector have been used. The influence of variables such as mobile-phase composition and flow-rate, has been studied. An acetonitrile-aqueous solution of oxalic acid 4x10(-4) M (28:72, v/v) has been selected as optimum. The wavelength for the photometric detection of the six antibiotics was 265 nm. For the fluorimetric detection two pairs of excitation/emission wavelengths, 260/360 or 270/440 nm, were selected for the determination of nalidixic acid, 7-hydroxymethylnalidixic acid and oxolinic acid, and for the determination of pipemidic acid and cinoxacin, respectively. The analytical parameters and detection and quantification limits of the method have been determined. The proposed method has been applied for the determination of the six compounds in urine, applying different procedures depending on their concentration, the results being very acceptable.

Time-dependent elimination of cinoxacin in rats.

The effect of the variation of urinary pH on the pharmacokinetics of the acidic antibacterial agent, cinoxacin (pKa 4.60), was examined. Urinary pH of 24-h fasted rats remained at about pH 6 during the daytime, while that of nonfasted rats was high (about pH 7.5) in the morning and gradually decreased to a pH similar to that of the fasted rat in the afternoon. The free fraction of cinoxacin in fasted rat sera in the morning was similar to that in nonfasted rats despite the longer half-life of cinoxacin in fasted rats. In the afternoon the free fraction was slightly different despite similar cinoxacin elimination in fasted and nonfasted rats. These findings seemed to exclude the contribution of protein binding from the causes of increased cinoxacin elimination in nonfasted rats in the morning. Elimination rate constants of cinoxacin obtained with a one-compartment open model correlated well with urinary pH 30 min after injection, suggesting that the urinary pH plays a more important role in cinoxacin elimination. When cinoxacin was orally administered to fasted rats at 11:00, the area under the plasma concentration-time curve was threefold larger than in nonfasted rats. As found with the intravenous administration, this difference may be explained by the prolonged half-life caused by decreased urinary pH after fasting. This study revealed the time-dependent elimination of cinoxacin in nonfasted rats, which is related to physiological change of urinary pH caused by food intake.

Cinoxacin: pharmacokinetics and tolerance in patients with normal and impaired renal function.

The pharmacokinetics of cinoxacin, a new antibacterial compound related to nalidixic acid and oxolinic acid, were investigated in 22 patients with varying degrees of renal impairment. After oral administration of cinoxacin at 500 mg every 12 h for 7 days to all patients, the drug was found to be well tolerated. The urine concentrations of cinoxacin in all patients far exceeded the minimal inhibitory concentrations for susceptible organisms commonly found in urinary tract infections. The serum half-life of cinoxacin in patients with normal renal function was approximately 2.7 h but increased to approximately 8.5 h in patients with creatinine clearance less than 30 ml/min. No undue drug accumulation was demonstrated in any patient group during the treatment. Highly significant correlations were found between the elimination rate constant and creatinine clearance and also between the elimination half-life and serum creatinine. The bioavailability of cinoxacin was independent of renal function.