Distribution characteristics of clarithromycin and azithromycin, macrolide antimicrobial agents used for treatment of respiratory infections, in lung epithelial lining fluid and alveolar macrophages

Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Hokkaido Pharmaceutical University, 7-1 Katsuraoka-cho, Otaru, Hokkaido 047-0264, Japan.
Biopharmaceutics & Drug Disposition (Impact Factor: 2.34). 10/2011; 32(7):389-97. DOI: 10.1002/bdd.767
Source: PubMed


The distribution characteristics of clarithromycin (CAM) and azithromycin (AZM), macrolide antimicrobial agents, in lung epithelial lining fluid (ELF) and alveolar macrophages (AMs) were evaluated. In the in vivo animal experiments, the time-courses of the concentrations of CAM and AZM in ELF and AMs following oral administration (50 mg/kg) to rats were markedly higher than those in plasma, and the area under the drug concentration-time curve (AUC) ratios of ELF/plasma of CAM and AZM were 12 and 2.2, and the AUC ratios of AMs/ELF were 37 and 291, respectively. In the in vitro transport experiments, the basolateral-to-apical transport of CAM and AZM through model lung epithelial cell (Calu-3) monolayers were greater than the apical-to-basolateral transport. MDR1 substrates reduced the basolateral-to-apical transport of CAM and AZM. In the in vitro uptake experiments, the intracellular concentrations of CAM and AZM in cultured AMs (NR8383) were greater than the extracellular concentrations. The uptake of CAM and AZM by NR8383 was inhibited by ATP depletors. These data suggest that the high distribution of CAM and AZM to AMs is due to the sustained distribution to ELF via MDR1 as well as the high uptake by the AMs themselves via active transport mechanisms.

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    • "In addition, local transporters, ie, the MDR1/P-glycoprotein substrate, play a major role in transporting drug molecules from the alveolar region to the blood circulation, and the inverse.87–91 It has been observed that it is easier for a molecule to be transported from the alveolus to the circulation than the inverse.91 Therefore, at least for the clarithromycin aerosol formulation, it has been demonstrated that systemic side effects are fewer because less drug is introduced into the systemic circulation. "
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    ABSTRACT: Currently almost all antibiotics are administered by the intravenous route. Since several systems and situations require more efficient methods of administration, investigation and experimentation in drug design has produced local treatment modalities. Administration of antibiotics in aerosol form is one of the treatment methods of increasing interest. As the field of drug nanotechnology grows, new molecules have been produced and combined with aerosol production systems. In the current review, we discuss the efficiency of aerosol antibiotic studies along with aerosol production systems. The different parts of the aerosol antibiotic methodology are presented. Additionally, information regarding the drug molecules used is presented and future applications of this method are discussed.
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    • "Aliquots of samples were taken from the apical or the basolateral side every 30 min for 2 hr and were replaced with equal volumes of drug-free HBSS. The concentrations of CAM, AZM and TEL in each sample were measured by HPLC as reported previously (Togami et al. 2009, 2011). The transported amounts of antibiotics were determined and the apparent permeability "
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    ABSTRACT: We have shown that clarithromycin (CAM), a macrolide antibiotic, more highly distributes from plasma to lung epithelium lining fluid (ELF), the infection site of pathogens, than azithromycin (AZM) and telithromycin (TEL). Transporter(s) expressed on lung epithelial cells may contribute to the distribution of the compiunds to the ELF. However, distribution mechanisms are not well known. In this study, their transport characteristics in Calu-3 cell monolayers as model lung epithelial cells were examined. The basolateral-to-apical transport of CAM through Calu-3 cell monolayers was greater than that of AZM and TEL. Although verapamil and cyclosporine A as MDR1 substrates completely inhibited the basolateral-to-apical transport, probenecid as MRP1 inhibitor did not show an effect. These results suggest that the antibiotics are transported from plasma to ELF by MDR1 of lung epithelial cells. In addition, their affinity and binding rate to MDR1 was examined by ATP activity assay. The affinity and binding rate of CAM was greater than those of AZM and TEL. These corresponded with the distributions from plasma to ELF as described above. The present study suggests that the more highly distribution of CAM from plasma to ELF is due to the high affinity and binding rate to MDR1 of lung epithelial cells.
    Preview · Article · May 2012 · Pharmazie
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    • "The drawback of the use of these agents is their significantly higher cost when compared to erythromycin, which is a relatively cheap and effective drug. Macrolide concentrations are at least 10-fold higher in epithelial lung fluid than in serum [44]. "
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