title: Distribution characteristics of telithromycin, a novel ketolide antimicrobial agent applied for treatment of respiratory infection, in lung epithelial lining fluid and alveolar macrophages.
abstract: The distribution characteristics of telithromycin (TEL), a novel ketolide antimicrobial agent, in lung epithelial fluid (ELF) and alveolar macrophages (AMs) were evaluated. In vivo animal experiments, the time-courses of the concentrations of TEL in ELF and AMs following oral administration of TEL solution (50 mg/4 mL/kg) to rats were markedly higher than in plasma, and areas under drug concentration-time curve (AUC) ratios of ELF/plasma and AMs/plasma were 2.4 and 65.3, respectively. In vitro transport experiments, the basolateral-to-apical transport of TEL through model lung epithelial cell (Calu-3) monolayers was greater than apical-to-basolateral transport. Rhodamine123 and verapamil, MDR1 substrates, reduced the basolateral-to-apical transport of TEL. In vitro uptake experiments, the intracellular equilibrated concentration of TEL in cultured AMs (NR8383) was approximately 40 times the extracellular concentration. The uptake of TEL by NR8383 was inhibited by rotenone and FCCP, ATP depletors and was temperature-dependent. These data suggest that the high distribution of TEL to AMs is due to the sustained distribution to ELF via MDR1 as well as the high uptake by AMs themselves via active transport mechanisms.
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Hokkaido Pharmaceutical University, Hokkaido, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Togami
authors.forename: Sumio
authors.initials: S
authors.lastname: Chono
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Seki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Morimoto
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002460:Cell Line; D017291:Clarithromycin / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D048628:Ketolides / Q000493:pharmacokinetics*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000494:pharmacology
chemical_list: D048628:Ketolides; D012402:Rotenone; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D017291:Clarithromycin; C106791:telithromycin