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: 2.18). 08/2011; 32(7):389-97. DOI: 10.1002/bdd.767
Source: PubMed

ABSTRACT 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.

1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and Objective: Ureaplasma spp. infection has been associated with bronchopulmonary dysplasia (BPD) in preterm infants. Macrolides have been used for the treatment of Ureaplasma spp. infection, with an intention to prevent BPD. The objective of this meta-analysis is to evaluate the use of macrolides in the prevention of BPD in preterm infants. Methods: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials, abstracts of the major pediatric society meetings and bibliographies of retrieved articles. We included randomized controlled trials assessing the effects of macrolides therapy on BPD in preterm infants. A random/fixed-effect model was used to synthesize predefined outcomes. Results: Six studies involving 469 preterm infants were eligible for the analysis. Macrolides when used prophylactically (4 studies) did not show significant reduction in BPD (risk ratio, RR, 0.88, 95% confidence interval, CI, 0.75-1.03), death (RR 0.89, 95% CI 0.79-1.01) or in the composite outcome of BPD/death. Similarly, there was no significant reduction in BPD (RR 0.64, 95% CI 0.31-1.31) or the composite outcome of BPD/death (RR 0.41, 95% CI 0.05-3.13), when macrolides were used in Ureaplasma-positive infants. However, prophylactic azithromycin therapy (3 studies) was associated with significant reduction in BPD (RR 0.83, 95% CI 0.71-0.97; number needed to treat, NNT, 10) and composite outcome of BPD/death (RR 0.86, 95% CI 0.77-0.97; NNT 10). Conclusion: This meta-analysis demonstrates prophylactic azithromycin therapy was associated with statistically significant reduction in BPD and the composite outcome of BPD/death in preterm infants. However, given the limited information on pharmacokinetics and potential harmful effects, further studies should be done before routine use of azithromycin in the neonatal population. © 2014 S. Karger AG, Basel.
    Neonatology 10/2014; 106(4):337-347. · 2.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Solithromycin is a 4th generation macrolide/fluoroketolide antibiotic that has potential applications in the treatment and prevention of intrauterine and fetal infections in pregnancy; it has also been reported to exert anti-inflammatory effects. The objective of the present study was to determine its ability to cross the human placenta and inhibit cytokine production by placental and decidual cells in culture.
    Placenta 09/2014; · 3.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We examined the involvement of intestinal permeability in the oral absorption of clarithromycin (CAM), a macrolide antibiotic, and telithromycin (TEL), a ketolide antibiotic, in the presence of efflux transporters. To independently examine the intestinal and hepatic availability, we administered CAM and TEL (10 mg/kg) orally, intraportally, and intravenously to rats. The intestinal and hepatic availability was calculated from the area under the plasma concentration-time curve (AUC) after administration of CAM and TEL via different routes. The intestinal availabilities of CAM and TEL were lower than their hepatic availabilities. The intestinal availability after oral administration of CAM and TEL increased by 1.3- and 1.6-fold, respectively, after concomitant oral administration of verapamil as a P-glycoprotein (P-gp) inhibitor. Further, we performed an in vitro transport experiment using the Caco-2 cell monolayers as a model of intestinal epithelial cells. The apical-to-basolateral transport of CAM and TEL through the Caco-2 cell monolayers was lower than their basolateral-to-apical transport. Verapamil and bromosulfophthalein as a multidrug resistance-associated proteins (MRPs) inhibitor significantly increased the apical-to-basolateral transport of CAM and TEL. Thus, our results suggest that oral absorption of CAM and TEL is dependent on intestinal permeability that may be limited by P-gp and MRPs on the intestinal epithelial cells. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 05/2014; · 2.18 Impact Factor