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Pharmacokinetics and biliary concentrations of fleroxacin in cholecystectomized patients
W L Hayton1, V Vlahov, N Bacracheva
1College of Pharmacy, Washington State University, Pullman 99164-6510.
Abstract:
Patients with biliary tract infections received 800 mg of fleroxacin orally once daily on five consecutive days; cholecystectomy was on day 3. Starting on the day when dose 5 was administered, serial blood and T-drain bile samples were taken for 72 h and urine was collected for 96 h. The mean (+/- the standard deviation) peak concentration in plasma was 8.2 +/- 4.0 mg/liter at 8.3 h. The harmonic mean elimination half-life was 10.5 h, which is comparable to that reported for healthy volunteers. This increase resulted from reduced renal clearance (mean [+/- standard deviation], 38 +/- 22 ml/min), as the volume of distribution in the patients (1.4 +/- 0.7 liter/kg) did not differ from that reported for healthy subjects. Maximum concentrations in T-drain bile were high (median, 22.1 mg/liter) and exceeded those measured in plasma by a factor of 2 to 3; the individual ratios of the area under the curve for bile divided by that for plasma ranged from 1.3 to 9.9. As observed in healthy volunteers, the major pathway for elimination of fleroxacin was via the kidneys. The fraction of dose 5 eliminated in the 0- to 24-h urine was reduced, however, and the fraction of the dose in the urine as the N-demethyl and N-oxide metabolites was elevated. At the dose regimen used in this study, the MICs for most pathogens that cause biliary tract infections were surpassed in plasma and bile for more than 24 h.
Insights
Fleroxacin in biliary tract infections achieved therapeutic levels in plasma and bile for over 24 hours. Reduced renal clearance and altered metabolism were observed in patients, impacting drug elimination.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Infectious Diseases
- Gastroenterology
Background:
- Biliary tract infections (BTIs) are serious conditions requiring effective antimicrobial therapy.
- Fleroxacin is a fluoroquinolone antibiotic with activity against common BTI pathogens.
- Understanding fleroxacin's pharmacokinetic profile in BTIs is crucial for optimizing treatment.
Purpose of the Study:
- To evaluate the pharmacokinetic profile of oral fleroxacin in patients with biliary tract infections.
- To assess fleroxacin concentrations in plasma and T-drain bile.
- To investigate fleroxacin's elimination pathways and metabolite formation in this patient population.
Main Methods:
- Patients with BTIs received 800 mg oral fleroxacin daily for five days, with cholecystectomy on day 3.
- Serial blood, T-drain bile, and urine samples were collected post-dose 5.
- Plasma, bile, and urine concentrations were analyzed to determine pharmacokinetic parameters.
Main Results:
- Mean peak plasma concentration was 8.2 mg/L at 8.3 hours; elimination half-life was 10.5 hours.
- T-drain bile concentrations were high (median 22.1 mg/L), exceeding plasma by 2-3 fold.
- Reduced renal clearance (38 mL/min) and increased N-demethyl and N-oxide metabolites were observed.
Conclusions:
- Fleroxacin achieved concentrations above MICs for most BTI pathogens in plasma and bile for over 24 hours.
- Altered renal clearance and metabolism in BTIs necessitate consideration for dosing adjustments.
- Fleroxacin demonstrates potential efficacy for treating biliary tract infections.