High and prolonged pulmonary tissue concentrations of azithromycin following a single oral dose

cAlthough azithromycin is extensively used in the treatment of respiratory tract infections as well as skin and skin-related infections, pharmacokinetics of azithromycin in extracellular space fluid of soft tissues, i.e., one of its therapeutic target sites, are not yet fully elucidated. In this study, azithromycin concentration-time profiles in extracellular space of muscle and subcutaneous adipose tissue, but also in plasma and white blood cells, were determined at days 1 and 3 of treatment as well as 2 and 7 days after the end of treatment. Of all compartments, azithromycin concentrations were highest in white blood cells, attesting for intracellular accumulation. However, azithromycin concentrations in both soft tissues were markedly lower than in plasma both during and after treatment. Calculation of the area under the concentration-time curve from 0 to 24 h (AUC 0 -24 )/MIC 90 ratios for selected pathogens suggests that azithromycin concentrations measured in the present study are subinhibitory at all time points in both soft tissues and at the large majority of observed time points in plasma. Hence, it might be speculated that azithromycin's clinical efficacy relies not only on elevated intracellular concentrations but possibly also on its known pleotropic effects, including immunomodulation and influence on bacterial virulence factors. However, prolonged subinhibitory azithromycin concentrations at the target site, as observed in the present study, might favor the emergence of bacterial resistance and should therefore be considered with concern. In conclusion, this study has added important information to the pharmacokinetic profile of the widely used antibiotic drug azithromycin and evidentiates the need for further research on its potential for induction of bacterial resistance.

Section: Discussioncontrasting

confidence: 96%

mentioning

confidence: 99%

Blood, Tissue, and Intracellular Concentrations of Azithromycin during and after End of Therapy

Matzneller

Krasniqi

Kinzig

et al. 2013

“…The contribution of the CL BILE and CL R to the CL SYS of azithromycin was relatively small (Ͻ25%), suggesting the possibility of the presence of other, unknown elimination routes of azithromycin. Considering that azithromycin is characterized as a drug with exceptionally high accumulation in tissues (7,19), it could be inferred that the metabolism and/or decomposition in the tissue cells or excretion by breath and sweat may be the other elimination routes for azithromycin. Further studies are needed to clarify the other elimination routes of azithromycin.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that many macrolide antibiotics, including erythromycin and clarithromycin, can overcome P-glycoprotein-dependent anticancer drug resistance and cause profound alterations in the pharmacokinetics of doxorubicin and grepafloxacin, which are substrates for P glycoprotein (15,35,38). Azithromycin possesses unique pharmacokinetic characteristics with a longer half-life, greater tissue distribution, and higher intracellular concentration than other known macrolide antibiotics (7,9,19). This antibiotic is mainly eliminated in unchanged form in the feces via biliary excretion and intestinal secretion, whereas urinary excretion is the minor elimination route in humans (26).…”

mentioning

confidence: 99%

Possible Involvement of the Drug Transporters P Glycoprotein and Multidrug Resistance-Associated Protein Mrp2 in Disposition of Azithromycin

Sugie

Asakura

Zhao

et al. 2004

100

P glycoprotein and multidrug resistance-associated protein 2 (Mrp2), ATP-dependent membrane transporters, exist in a variety of normal tissues and play important roles in the disposition of various drugs. The present study seeks to clarify the contribution of P glycoprotein and/or Mrp2 to the disposition of azithromycin in rats. The disappearance of azithromycin from plasma after intravenous administration was significantly delayed in rats treated with intravenous injection of cyclosporine, a P-glycoprotein inhibitor, but was normal in rats pretreated with intraperitoneal injection erythromycin, a CYP3A4 inhibitor. When rats received an infusion of azithromycin, cyclosporine and probenecid, a validated Mrp2 inhibitor, significantly decreased the steady-state biliary clearance of azithromycin to 5 and 40% of the corresponding control values, respectively. However, both inhibitors did not alter the renal clearance of azithromycin, suggesting the lack of renal tubular secretion of azithromycin. Tissue distribution experiments showed that azithromycin is distributed largely into the liver, kidney, and lung, whereas both inhibitors did not alter the tissue-to-plasma concentration ratio of azithromycin. Significant reduction in the biliary excretion of azithromycin was observed in Eisai hyperbilirubinemic rats, which have a hereditary deficiency in Mrp2. An in situ closed-loop experiment showed that azithromycin was excreted from the blood into the gut lumen, and the intestinal clearance of azithromycin was significantly decreased by the presence of cyclosporine in the loop. These results suggest that azithromycin is a substrate for both P glycoprotein and Mrp2 and that the biliary and intestinal excretion of azithromycin is mediated via these two drug transporters.P glycoprotein, an ATP-binding cassette transport protein, exists constitutively in a variety of normal tissues such as the liver, kidney, small intestine, and capillary endothelium in the brain (22,23,30) and plays an important role in the disposition of hydrophobic and cationic anticancer drugs. Like P glycoprotein, multidrug resistance-associated protein 2 (Mrp2) is also expressed in almost the same tissues as P glycoprotein (4, 16). This drug-transporting protein also acts as an active efflux pump for a wide range of organic anions, such as glutathione, glucuronate, and sulfate conjugates, by an ATP-dependent mechanism (20). Thus, both drug transporters appear to play key roles in the absorption, distribution, and elimination of various drugs.It is known that the macrolide antibiotics erythromycin and clarithromycin inhibit not only CYP3A4 but also P glycoprotein (11,21,34,37). We previously reported that many macrolide antibiotics, including erythromycin and clarithromycin, can overcome P-glycoprotein-dependent anticancer drug resistance and cause profound alterations in the pharmacokinetics of doxorubicin and grepafloxacin, which are substrates for P glycoprotein (15,35,38). Azithromycin possesses unique pharmacokinetic characteristics with a longer h...

“…Several studies have demonstrated that levofloxacin and azithromycin penetrate well into the lung tissues (7,19,24,29,41). Since these studies used whole tissue samples, intrapulmonary drug penetration into different compartments (e.g., extravascular and intracellular) of the lung was not determined.…”

mentioning

confidence: 99%

Steady-State Plasma and Bronchopulmonary Concentrations of Intravenous Levofloxacin and Azithromycin in Healthy Adults

Rodvold

Danziger

Gotfried

2003

The purpose of this study was to compare the concentrations of levofloxacin and azithromycin in steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) after intravenous administration. Thirtysix healthy, nonsmoking adult subjects were randomized to either intravenous levofloxacin (500 or 750 mg) or azithromycin (500 mg) once daily for five doses. Venipuncture and bronchoscopy with bronchoalveolar lavage were performed in each subject at either 4, 12, or 24 h after the start of the last antibiotic infusion. The mean concentrations of levofloxacin and azithromycin in plasma were similar to those previously published. The dosing regimens of levofloxacin achieved significantly (P < 0.05) higher concentrations in steady-state plasma than azithromycin during the 24 h after drug administration. The respective mean (؎ standard deviation) concentrations at 4, 12, and 24 h in ELF for 500 mg of levofloxacin were 11.01 ؎ 4.52, 2.50 ؎ 0.97, and 1.24 ؎ 0.55 g/ml; those for 750 mg of levofloxacin were 12.94 ؎ 1.21, 6.04 ؎ 0.39, and 1.73 ؎ 0.78 g/ml; and those for azithromycin were 1.70 ؎ 0.74, 1.27 ؎ 0.47, and 2.86 ؎ 1.75 g/ml. The differences in concentrations in ELF among the two levofloxacin groups and azithromycin were significantly (P < 0.05) higher at the 4-and 12-h sampling times. The respective concentrations in AM for 500 mg of levofloxacin were 83.9 ؎ 53.2, 18.3 ؎ 6.7, and 5.6 ؎ 3.2 g/ml; those for 750 mg of levofloxacin were 81.7 ؎ 37.0, 78.2 ؎ 55.4, and 13.3 ؎ 6.5 g/ml; and those for azithromycin were 650 ؎ 259, 669 ؎ 311, and 734 ؎ 770 g/ml. Azithromycin achieved significantly (P < 0.05) higher concentrations in AM than levofloxacin at all sampling times. The concentrations in ELF and AM following intravenous administration of levofloxacin and azithromycin were higher than concentrations in plasma. Further studies are needed to determine the clinical significance of such high intrapulmonary concentrations in patients with respiratory tract infections.