Single-dose intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime in volunteer subjects

Abstract

The intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime were studied in 68 volunteers who received single, oral doses of azithromycin (0.5 g), clarithormycin (0.5 g), ciprofloxacin (0.5 g), or cefuroxime (0.5 g). In subgroups of four subjects each, the subjects underwent bronchoscopy and bronchoalveolar lavage at timed intervals following drug administration. Drug concentrations, including those of 14-hydroxyclarithromycin (14H), were determined in serum, bronchoalveolar lavage fluid, and alveolar cells (ACs) by high-pressure liquid chromatography. Concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. The maximum observed concentrations (mean +/- standard deviation) of azithromycin, clarithromycin, 14H, ciprofloxacin, and cefuroxime in serum were 0.13 +/- 0.07, 1.0 +/- 0.6, 0.60 +/- 0.41, 0.95 +/- 0.32, and 1.1 +/- 0.3 microgram/ml, respectively (all at 6 h). None of the antibiotics except clarithromycin (39.6 +/- 41.1 micrograms/ml) was detectable in ELF at the 6-h bronchoscopy. The movement into and persistence in cells was different for azithromycin and clarithromycin. In ACs azithromycin was not detectable at 6 h, reached its highest concentration at 120 h, and exhibited the greatest area under the curve (7,403 micrograms.hr ml-1). The peak concentration of clarithromycin (181 +/- 94.1 micrograms/ml) was greater and occurred earlier (6 h), but the area under the curve (2,006 micrograms.hr ml-1) was less than that observed for azithromycin. 14H was detectable in ACs at 6 h (40.3 +/- 5.2 micrograms/ml) and 12 h (32.8 +/- 57.2 micrograms/ml). The peak concentration of ciprofloxacin occurred at 6 h (4.3 +/- 5.2 micrograms/ml), and the area under the curve was 35.0 micrograms.hr ml-1. The data indicate that after the administration of a single dose, azithromycin, clarithromycin, and ciprofloxacin penetrated into ACs in therapeutic concentrations and that only clarithromycin was present in ELF. The correlation of these kinetic observations with clinical efficacy or toxicity was not investigated and is unclear, but the data provide a basis for further kinetic and clinical studies.

Steady-state serum and intrapulmonary pharmacokinetics and pharmacodynamics of tigecycline

“…The amount of epithelial lining fluid recovered was calculated by the urea dilution method as described by Rennard et al [19], and as reported in our previous pulmonary pharmacokinetic studies [12][13][14][15][16][17]. The concentration of urea in serum was analysed by the clinical laboratory at UCSF using a coupled urease-glutamate dehydrogenase (GLDH) enzymatic method, modified by Boehringer Mannheim Corporation (Indianapolis, IN) [20].…”

“…Measurements were made at a fixed time interval permitting automated analysis with a BM 747 Analyzer (Boehringer Mannheim). Urea was measured in BAL supernatant utilizing a modified enzymatic assay (Infinity BUN kit UV-63, Sigma, St. Louis, MO) as previously reported [12][13][14][15][16][17]. The assay was linear (R 2 = 0.99) for concentrations of urea in BAL from 0.047 to 0.750 mg/dL.…”

“…Standardized bronchoscopy, bronchoalveolar lavage and clinical monitoring [12][13][14][15][16][17] were performed in the GCRC at 2, 3, 4, 6, 12 and 24 h after the administration of the last dose. Systemic sedation was not used.…”

“…In human plasma, mean percentages of protein-bound [ 14 C]-tigecycline were 78.7% and 88.6% at nominal total tigecycline concentrations of 0.1 and 1.0 g/mL, respectively, and were concentration-dependent (Joseph McDevitt, Wyeth Research, Collegeville, PA, USA, August 2004, personal communication). Tigecycline is currently being studied for the treatment of nosocomial and community acquired pneumonia but its in vivo penetration into pulmonary alveolar cells (AC) and pulmonary epithelial lining fluid (ELF) in humans has not been reported.We have previously reported [12][13][14][15][16][17] our techniques for the in vivo measurement of the concentration of antibiotics in ELF and AC. The purpose of this investigation was to determine the steady-state serum and intrapulmonary pharmacokinetic and pharmacodynamic parameters of intravenously administered tigecycline in healthy subjects.…”

Inhaled Drug Delivery for Tuberculosis Therapy

“…1 A). High EMB and macrolide concentrations were achieved in BAL cells relative to plasma when these drugs were administered orally to human subjects (107)(108)(109); whereas, rifapentine achieves substantially lower concentrations in the lungs than observed in plasma. Patients being treated for pulmonary TB may have suboptimal drug concentration intracellularly, thus predisposing them to development of drug-resistant strains of micro-organism (110).…”