Altered disposition of fleroxacin in patients with cystic fibrosis.

Thirteen patients with cystic fibrosis and 12 healthy control volunteers received a single oral 800 mg dose of fleroxacin and 800 mg every day for 5 days. Interstitial fluid penetration was studied by the suction-induced blister technique. Fleroxacin and its two major metabolites, N-demethyl and N-oxide, were analyzed in plasma and urine by HPLC. Single-dose absorption parameters (absorption rate constant, normalized peak plasma drug concentration, and time to reach peak concentration) and total urinary excretion indicated that fleroxacin was absorbed more slowly and more completely in patients with cystic fibrosis than in control subjects. Fleroxacin volume of distribution tended to be smaller in patients with cystic fibrosis and it reached statistical significance after a single dose when normalization for lean body mass was applied. When normalized for lean body mass, the formation clearance of N-demethyl fleroxacin and N-oxide fleroxacin was significantly greater in patients with cystic fibrosis than in control subjects (p less than 0.05). These data concur with those of others showing an induction of drug-metabolizing enzymes in cystic fibrosis. Renal clearances of fleroxacin and its metabolites were significantly increased in cystic fibrosis (p less than 0.05), and this seems to be explained by a decreased tubular reabsorption of these compounds. The differences seen in the pharmacokinetics of fleroxacin in cystic fibrosis support the theories of generalized induction of drug metabolism and of a defective renal tubular reabsorptive process of drugs in cystic fibrosis.

Pleural penetration of ciprofloxacin in patients with empyema thoracis.

We evaluated the pharmacokinetics of a single 200-mg dose of ciprofloxacin, administered as a 30-minute infusion, into pleural exudate in five elderly patients with empyema thoracis. Ciprofloxacin was measured by HPLC and the pharmacokinetic parameters were determined by noncompartmental methods. Mean peak serum levels 30 minutes after administration were 1.98 +/- 0.07 mg/L. Terminal serum half-lives ranged from 3.9 to 5.1 h. Mean concentrations of ciprofloxacin in pleural exudate were 1.44 +/- 0.42 mg/L at a mean time of 4.5 +/- 2.5 h. After this time, the pleural exudate level exceeded the corresponding serum twofold to tenfold. The mean percentage penetration into the inflammatory compartment was approximately 210 percent. Our data suggested that ciprofloxacin penetrates well into the pleural fluid of patients with empyema thoracis. The concentrations achieved were well above the MIC90 of most pathogens normally found in patients with empyema thoracis for a period of approximately 12 h.

Pharmacokinetics and body fluid penetration of fleroxacin in healthy volunteers.

The pharmacokinetics of fleroxacin after oral administration of 400 mg fleroxacin in twelve healthy volunteers were investigated. All drug analysis was carried out by HPLC. Pharmacokinetic analysis was done by non-compartmental methods. We found that fleroxacin achieves high plasma levels of 5.2 +/- 1.1 mg/l after 1.2 +/- 0.7 h. The high AUC-value of 60.4 +/- 8.4 mg.h/l is the result of complete absorption and the long half-life of 10.8 +/- 1.6 h. The total, renal and non-renal clearance of fleroxacin were 107.9 +/- 15.1, 67.6 +/- 11.8 and 40.3 +/- 14.5 ml/min respectively. The volume of distribution Vd beta/F was 101.4 +/- 21.9 or 1.32 +/- 0.28 l/kg. Fleroxacin penetrated well into saliva (66%), nasal secretions (223%), tears (69%) and sweat (43%). On the basis of these findings once a day administration deserves consideration in the further clinical development of fleroxacin.

Metabolism of fleroxacin in man.

The metabolism of fleroxacin was studied in 12 healthy volunteers by use of a newly developed high pressure liquid chromatographic assay. Desmethylfleroxacin and fleroxacin N-oxide were identified as the major metabolites of fleroxacin in plasma and urine. The maximum concentrations of fleroxacin, desmethylfleroxacin and fleroxacin N-oxide in plasma were 5.2 +/- 1.1, 0.0683 +/- 0.0151 and 0.0634 +/- 0.0090 mg/l reached at 1.2 +/- 0.7 h, 2.2 +/- 0.8 h and 6.2 +/- 2.4 h respectively (one subject excluded from analysis). The plasma AUC was between 1.0 and 2.6 mg.h/l for either metabolite and between 47.9 and 75.1 mg.h/l for the parent compound. The terminal half-life of desmethylfleroxacin was higher than that of unchanged fleroxacin and similar to the half-life of fleroxacin N-oxide. In urine unchanged fleroxacin, desmethylfleroxacin and fleroxacin N-oxide accounted for 59.9%, 6.8% and 6.3% of the dose of fleroxacin. The renal clearance of fleroxacin, desmethylfleroxacin and fleroxacin N-oxide were 67.6, 300.9 and 324.8 ml/min respectively. We conclude that demethylation and N-oxidation of fleroxacin affects the distribution and elimination characteristics significantly. Renal clearance increased, and it is suggested that the volume of distribution may increase also.