Departments of 1 Otolaryngology, Head and Neck Surgery and 2 Department of Pharmacology, University of Regensburg, D-93053 Regensburg, Germany
Received 20 September 2004; returned 28 October 2004; revised 24 November 2004; accepted 27 December 2004
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Abstract |
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Patients and methods: A total of 29 patients undergoing rhinosurgery for chronic sinusitis were evaluated. Samples of blood, nasal mucus, nasal mucosa and ethmoid bone were collected during surgery in groups of 56 patients after 3, 6, 9, 15 and 24 h following a single oral dose of 800 mg telithromycin. Drug concentrations were determined by HPLC with fluorimetric detection.
Results: The highest telithromycin concentrations were observed after 3 h in plasma as well as in all tissues sampled. The mean plasma concentrations were 0.73 mg/L in the 3 h group and 0.02 mg/L in the 24 h group. The concomitant tissue concentrations were higher. The tissue penetration, expressed by the ratio of the area under the concentrationtime curve in tissue versus plasma, was 1.0 for nasal mucus, 5.9 for nasal mucosa and 1.6 for ethmoid bone.
Conclusions: Telithromycin achieved tissue concentrations that were generally above the MIC90 for common pathogens in upper respiratory tract infections. These results indicate that telithromycin diffuses rapidly into the nasal tissues and achieves high and prolonged concentrations in nasal mucosa and ethmoid bone.
Keywords: ketolides , pharmacokinetics , nasal tissue
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Introduction |
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The aim of the present study was to investigate the penetration of telithromycin into the nasal mucosa and ethmoid bone of patients, to provide kinetic data supporting the use of telithromycin in upper respiratory tract infections, as well as data on the penetration of telithromycin in rarely investigated tissues such as bone.
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Materials and methods |
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This was a single-centre, parallel-group, open-label trial in patients undergoing functional endoscopic sinus surgery, and in some cases additional septoplasty, for chronic sinusitis. Exclusion criteria included significant hepatic and renal disorder, therapy with enzyme inductors within 2 weeks prior to telithromycin administration or concomitant medication with CYP3A4 substrates such as cisapride, ergot alkaloids, terfenadine or statins. Subjects were divided into five groups based on sampling times at 3, 6, 9, 15 and 24 h after a single oral dose of telithromycin 800 mg. The study was approved by the ethics committee of the University Hospital of Regensburg, and all subjects gave written informed consent. Samples of blood, nasal mucus, nasal mucosa and ethmoid bone were collected during the surgical procedure. Blood was collected into tubes containing EDTA as anticoagulant (EDTA Monovette; Sarstedt, Nümbrecht, Germany) and centrifuged to obtain plasma. Nasal mucus was obtained by suction; contamination with differing volumes of rinsing saline was not always avoidable. The mucus was absorbed onto a cellulose tampon (Salivette; Sarstedt, Nümbrecht, Germany), and a clear liquid was obtained by centrifugation. The ethmoid bone was rinsed briefly with saline to remove blood, and swabbed. Loosely adherent mucosa was carefully removed with a scalpel. All specimens were stored frozen at 25 °C until assay.
Drugs and chemicals
Telithromycin tablets (400 mg, batch no. 1 A009; expiry date 05/2005; Aventis Pharma Germany, Bad Soden) were obtained from the pharmacy of the University Hospital of Regensburg, Germany. Telithromycin (HMR 3647) and HMR 3004 were obtained from Aventis Pharma, Romainville, France. Acetonitrile and methanol (ultra gradient HPLC grade) were purchased from Baker, Groß-Gerau, Germany, and the other chemicals (analytical grade) were from E. Merck, Darmstadt, Germany. Water was purified with a Milli-Q water purification system (Millipore, Eschborn, Germany).
Drug assay
Drug concentrations were determined by HPLC with fluorimetric detection adapting a published method.7,8 Plasma or nasal mucus (200 µL) was mixed with 25 µL of internal standard solution (HMR 3004 100 µg/mL in methanol/water 50:50, v/v) and 400 µL of acetonitrile, for precipitation of proteins. Following centrifugation, the clear supernatant was injected onto the column. Mucosa (200300 mg) was homogenized with Ultraturrax (IKA, Breisgau, Germany) in eight volumes (w/v) of water/acetonitrile 30:70 (v/v) containing 5 µg/mL HMR 3004, followed by 30 min mixing using a horizontal shaker (SM30C, J. Otto, Tübingen, Germany). Bone (50150 mg) was deep frozen in liquid nitrogen and pulverized in a homemade, chilled, stainless steel mortar with pestle (type: Bessman Tissue Pulverizer, Spectrum Europe, Breda, The Netherlands). The bonemeal was then extracted using the horizontal shaker for 30 min in five volumes (w/v) of the tissue homogenization solution.
For chromatography, an LC-10A series HPLC system was used with Class10 software and an SPD-10A photometric detector (for HMR 3004) set at 300 nm, followed by an RF-10AXL fluorimetric detector (for telithromycin) set at excitation and emission wavelengths of 263 nm and 460 nm (Shimadzu, Duisburg, Germany). Separation was performed at 30 °C using a Nucleodur CN analytical column (internal diameter 150 x 4.6 mm; Macherey and Nagel, Düren, Germany) and an eluent consisting of 400 mL of 20 mM ammonium acetate, 0.20 mL of glacial acetic acid and 600 mL of acetonitrile. Telithromycin eluted after 4.5 min and the internal standard HMR 3004 after 5.1 min at a flow rate of 1.0 mL/min. The retention times of the analytes were about 10% shorter when the concentration of ammonium acetate was increased to 30 mM for the analysis of tissue. The recovery of telithromycin and HMR 3004 was quantitative from plasma and mucus, and 80%95% from tissue. However, the endogenous water content of the tissues was not taken into account for the calculation. Telithromycin adsorption at the cellulose tampon has been excluded by analysing spiked saline samples. The limit of quantification was 10 ng/mL in plasma and mucus and 30 ng/g in tissue, respectively. Accuracy and precision were better than 10% as determined by co-analysing appropriate quality control samples in spiked matrix.
Pharmacokinetic and statistical analysis
The area under the concentrationtime curve in plasma and tissue from 024 h (AUC024) was calculated using the linear trapezoidal rule. Descriptive statistics (mean ± S.D.) are reported for telithromycin.
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Results |
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The mean (± S.D.) telithromycin concentrations are listed in Table 1. The highest plasma and tissue concentrations were observed at the first sampling time 3 h after administration. Whereas the concentrations fell at comparable rates in plasma, mucosa and bone, the concentrations in nasal mucus showed a more variable concentrationtime course. The concentrations in mucosa and bone were higher compared with the concomitant plasma concentration throughout the sampling period. The mean tissue-to-plasma ratio was 5.2 for mucosa and 1.5 for bone after 3 h and increased to 14.5 and 2.6, respectively, after 24 h. Accordingly, the AUCs were higher in tissue compared with plasma (mucosa 24900 ng/mL·h, bone 6730 ng/mL·h, plasma 4230 ng/mL·h). The AUC in mucus (4280 ng/mL·h) was comparable with that in plasma. The ratio of the tissue versus plasma AUCs, a more robust parameter assessing tissue penetration, was 1.0 for mucus, 1.6 for bone and 5.9 for mucosa.
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Discussion |
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The results of this study show that telithromycin rapidly penetrated and achieved high concentrations in nasal tissue of surgical patients after a single oral dose of 800 mg. The relative systemic exposure, expressed by the ratio of the area under the concentrationtime curve in tissue versus plasma, was 5.9 for nasal mucosa and 1.6 for ethmoid bone, respectively. The tissue concentrations were higher than in plasma throughout the whole measuring period except for nasal mucus, where some specimens were potentially contaminated with rinsing saline, resulting in underestimated telithromycin concentrations. A moderate increase in the tissue-to-plasma concentration ratio was observed from 3 to 24 h, similar to that in tonsils,9 indicating prolonged tissue concentrations of telithromycin compared with plasma after a single dose. The tissue-to-plasma ratio was comparable with previous results in mucosa of paranasal sinuses or bronchial mucosa.1,10 The concentrations in nasal mucosa at 3 h were lower than those of clarithromycin after 250 mg twice a day,11 but the telithromycin tissue concentrations were more sustained, supporting the once-daily dosage regimen for telithromycin compared with twice-daily for clarithromycin.
To our knowledge, this is the first report of data on the penetration of telithromycin into human bone, and compared with the vast literature on the penetration of antibiotics into other various tissues, only a few studies describe the penetration of antibiotics into human bone.12 In general, fluoroquinolones and macrolides are considered antibiotics with good diffusion into bone tissue.13,14 In terms of the tissue-to-plasma concentration ratio, the best tissue penetration of all macrolides is shown for azithromycin, which provides bone concentrations exceeding the concomitant plasma concentrations several-fold, and is detectable in bone even 1 week after the last dose.1517 When considering absolute tissue concentrations, the highest concentrations in bone following therapeutic doses were described for roxithromycin with 5.1 µg/g.18 In our patients, the concentration of telithromycin in bone at 3 h was 1.1 µg/g. The tissue-to-plasma ratio was 1.5 in the 3 h group and 2.5 in the 24 h group, indicating that bone behaves as a deep compartment with delayed elimination.
In summary, the achieved concentrations of telithromycin in mucosa as well as in bone were generally above the MIC90 of common pathogens in upper respiratory tract infections (S. pneumoniae 0.12 mg/L, methicillin-susceptible Staphylococcus aureus 0.06 mg/L, M. catarrhalis 0.12 mg/L; data from the PROTEKT surveillance study).
We conclude that telithromycin diffuses rapidly into the nasal tissues and achieves high and prolonged concentrations in nasal mucosa and ethmoid bone that are maintained throughout the dosing period above the MIC90 of susceptible strains.
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Acknowledgements |
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References |
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