Pharmacokinetics and biliary concentrations of fleroxacin in cholecystectomized patients

Positron emission tomography (PET) with [18Fjfleroxacin was used to study the pharmacokinetics of fleroxacin, a new broad-spectrum fluoroquinolone, in 12 healthy volunteers (9 men and 3 women). The subjects were infused with a standard therapeutic dose of fleroxacin (400 mg) supplemented with -20 mCi of[18F]fleroxacin. Serial PET images were made and blood samples were collected for 8 h, starting at the initiation of the infusion. The subjects were then treated with unlabeled drug for 3 days (400 mg/day). On the fifth day, infusion of radiolabeled drug, PET imaging, and blood collection were repeated. In most organs, there was rapid accumulation of radiolabeled drug, with stable levels achieved within 1 h after completion of the infusion.Especially high peak concentrations (in micrograms per gram) were achieved in the kidney (>34), liver (>25), lung (>20), myocardium (>19), and spleen (>18). Peak concentrations of drug more than two times the MIC for 90% of Enterobacteriaceae strains tested (>10-fold for most organisms) were achieved in all tissues except the brain and remained above this level for more than 6 to 8 h. The plateau concentrations in tissues (2 to 8 h, in micrograms per gram ± standard error of the mean) of drug were as follows: brain, 0.

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confidence: 99%

Pharmacokinetics of [18F]fleroxacin in healthy human subjects studied by using positron emission tomography

Fischman

Livni

Babich

et al. 1993

“…The linearity ranges were 0.5 to 10 ,g/ml for plasma and bile and 0.05 to 150 ,ug/ml for urine. In plasma, precision ranged from 3.6% (4.2 ig/ml) to 8.5% (0.5 ,g/ml) for rufloxacin and was 5.6% (0.6 ,g/ml) for the N-desmethyl derivative. In urine, precision ranged from 2.2% (99.2 pg/ml) to 8.9% (20.6 ,ug/ml) for rufloxacin and from 2.3% (14.2 p,g/ml) to 4.0% (0.6 ,ug/ml) for the N-desmethyl derivative.…”

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confidence: 99%

“…Pharmacokinetic studies with both healthy subjects (9, 10, 12, 23) and patients with lower-respiratory-tract infections (4, 17) showed that rufloxacin is eliminated slowly, with a plasma half-life (tl,2) of about 35 h. The drug penetrates well into most tissues (1, 21, 23), and, because of its long t1,2, it can be administered once daily for treatment of urinary (14) and respiratory (5) tract infections. Clinically significant changes in the disposition of rufloxacin occur only in patients with severe renal (15) or hepatic (20) insufficiency.Although the importance of the concentration of antibiotics in bile for the treatment of biliary tract infections is still a matter of controversy, it is of interest to assess whether the oral administration of fluoroquinolone derivatives produces sufficient biliary concentrations to sterilize the infected bile (2,8). Similarly, a wide-spectrum antibacterial agent administered orally once a day could provide a valid choice for antibiotic prophylaxis in biliary-surgery and endoscopic procedures.…”

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confidence: 99%

“…Although the importance of the concentration of antibiotics in bile for the treatment of biliary tract infections is still a matter of controversy, it is of interest to assess whether the oral administration of fluoroquinolone derivatives produces sufficient biliary concentrations to sterilize the infected bile (2,8). Similarly, a wide-spectrum antibacterial agent administered orally once a day could provide a valid choice for antibiotic prophylaxis in biliary-surgery and endoscopic procedures.…”

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confidence: 99%

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Biliary excretion of rufloxacin in humans

Privitera

Nicastro

Imbimbo

et al. 1993

Rufloxacin is a new once-daily antibacterial fluoroquinolone with a long half-life. The aim of the present study was to evaluate the plasma and biliary kinetics and biliary and urinary excretion of rufloxacin in patients with extrahepatic cholestasis. Twelve patients with total external percutaneous transhepatic biliary drainage were given a single oral dose of 400 mg of rufloxacin. Plasma, bile, and urine samples and fractions were collected over 72 h after drug administration. Rufloxacin and its major metabolite, the N-desmethyl derivative, were measured by high-performance liquid chromatography. Maximum rufloxacin concentrations in plasma and bile (means + standard deviations) were 4.05 + 1.38 ,ug/ml and 8.24 + 7.16 p,g/ml, respectively, and were reached in 4.2 + 3.0 h and 4.2 + 3.5 h, respectively. The terminal elimination half-life of rufloxacin in plasma was 45.1 ± 13.5 h. Apparent plasma clearance was 31.3 + 10.5 ml/min, while biliary clearance was 0.4 ± 0.2 ml/min and renal clearance was 12.7 ± 6.0 ml/min. In 72 h, 0.9%o + 0.8% of the dose given was recovered in bile and 27.2% ± 12.0%O was recovered in urine. Biliary concentrations exceeded the MICs of most common biliary tract pathogens for at least 24 h after administration. The broad antibacterial spectrum of rufloxacin and its high and prolonged biliary concentrations suggest that this drug may be useful for treatment of biliary tract infections.Rufloxacin is a new oral fluoroquinolone characterized by a broad spectrum of activity against gram-negative and gram-positive aerobic bacteria (3). The antibacterial activity of rufloxacin is generally comparable to those of norfloxacin in vitro (13,22) and ciprofloxacin in in vivo models (7, 16). Pharmacokinetic studies with both healthy subjects (9, 10, 12, 23) and patients with lower-respiratory-tract infections (4, 17) showed that rufloxacin is eliminated slowly, with a plasma half-life (tl,2) of about 35 h. The drug penetrates well into most tissues (1, 21, 23), and, because of its long t1,2, it can be administered once daily for treatment of urinary (14) and respiratory (5) tract infections. Clinically significant changes in the disposition of rufloxacin occur only in patients with severe renal (15) or hepatic (20) insufficiency.Although the importance of the concentration of antibiotics in bile for the treatment of biliary tract infections is still a matter of controversy, it is of interest to assess whether the oral administration of fluoroquinolone derivatives produces sufficient biliary concentrations to sterilize the infected bile (2,8). Similarly, a wide-spectrum antibacterial agent administered orally once a day could provide a valid choice for antibiotic prophylaxis in biliary-surgery and endoscopic procedures. The aim of the present study was to investigate the pharmacokinetics and biliary excretion of rufloxacin in jaundiced patients with continuous complete external bile drainage through percutaneous transhepatic catheters.

“…In humans, concentrations of drug in body fluids and a small number of tissues have been measured (10,14,21,22,26), but detailed studies of tissue distribution have not been possible. To optimize the effective use of the drug in focal or systemic infections, it would be helpful to understand its pharmacokinetics in healthy and infected tissues.…”

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confidence: 99%

Pharmacokinetics of 18F-labeled fleroxacin in rabbits with Escherichia coli infections, studied with positron emission tomography

Fischman

Livni

Babich

et al. 1992

'8F-labeled fleroxacin was used to measure the pharmacokinetics of fieroxacin in healthy and infected animals by positron emission tomography (PET) and tissue radioactivity measurements. In all experiments, a pharmacological dose of unlabeled drug (10 mJkg) was coinjected with the tracer. The pharmacokinetics of [18FJfleroxacin was measured in groups of healthy mice (n = six per group) at 10, 30, 60, and 120 min after inijection and in groups of rats with Escherchia coli thigh infections (n = six per group) at 60 and 120 min after injection by radioactivity measurements in excised tissues. In healthy rabbits (n = 4) and in rabbits with E. coli thigh infections (n = 4), tissue concentrations of drug were determined by serial PET imaging over 2 h; after the final image was acquired, animals were sacrificed and concentrations measured by PET were compared with the results of tissue radioactivity measureinents. In all three species, there was rapid equilibration of[18F]fleroxacin to significant concentratiobs in most peripheral organs; low concentrations of drug were detected in the brain. Accumulations of radiolabeled drug in infected and healthy thigh muscles were similar. Peak concentrations of drug of more than three times the MIC for 90% of members of the family Enterobacteriaceae (>100-fold for most organisms) were achieved in all tissues except brain and remained above this level for more than 2 h. Especially high peak concentrations were achieved in the kidney (>75 ,ug/g), liver (>50 ,ug/g), blood (>25 ,g/g), and bone and lung (>10 Fg/g). Since the MICs for 90% of all Enterobacteriaceae are <2 ,ug/ml, fleroxacin should be particularly useful in treating gram-negative infections affecting these tissues. In contrast, the low concentration of drug delivered to the brain should limit the toxicity of the drug for the central nervous systens.