Transport of Azithromycin into Extravascular Space in Rats

Abstract

f Recent clinical trials showed a prolonged retention of subinhibitory concentrations of unbound azithromycin in the interstitial fluid of soft tissues despite the fact that azithromycin is extensively distributed in tissues. In these clinical trials, interstitial fluid samples were obtained by using the microdialysis method, and it was established that drug concentrations represent proteinunbound drug concentrations. The present study was designed to measure total azithromycin concentrations in the interstitial fluid of the skin of rats by directly collecting interstitial fluid samples from a pore formed on the skin by a dissolving microneedle array. The total azithromycin concentrations in interstitial fluid of the skin were about 4 to 5 times higher than those in plasma throughout the experimental period, and stasis of the azithromycin concentration in interstitial fluid was observed when the concentration of azithromycin in plasma was at the lower limit of quantification. In addition, the skin/plasma concentration ratio transiently increased after dosing (from 4.3 to 83.1). Our results suggest that azithromycin was trapped inside white blood cells and/or phagocytic cells in not only blood but also interstitial fluid, resulting in a high total azithromycin concentration and the retention of its antimicrobial activity at the primary infection site. The stasis of azithromycin in interstitial fluid and skin would lead to long-lasting pharmacological effects (including those against skin infection) at concentrations exceeding the MIC.

Pharmacokinetics of Macrolide Antibiotics and Transport into the Interstitial Fluid: Comparison among Erythromycin, Clarithromycin, and Azithromycin

“…A schematic of transport of three macrolides from blood circulation into extravascular space is illustrated in Figure 4. < 0.05 statistically significant difference vs. the data at 4 h. a) These results were previously reported in [12].…”

“…MRT, mean residence time. a) These results were previously reported in [12]. Figure 2 depicts the tissue distribution of EM and CAM after IV drug administration.…”

“…We observed a shorter t 1/2, z for EM and CAM than for AZM. The plasma concentrations of EM and CAM at 24 h after administration were not detectable, whereas AZM was detected at 72 h after administration [12]. The Vd values of EM and CAM were lower than that for AZM.…”

“…The distribution of the three macrolides was concentrated in the organs and peripheral tissues including the lung, liver, kidney, muscle, and skin. The drug concentrations in the tissues at each sampling time were much higher (EM: 2.0 to 10.3, CAM: 2.0 to 62.0, AZM: 4.3 to 1082.5 times [12]) than that in the plasma, whereas EM in the lung, liver, kidney and muscle was rapidly eliminated and under the limit of quantification (0.01 μg/g of tissues) at 8 h after administration to rats. Figure 3 depicts the total concentration profiles of EM and CAM in the plasma and ISF after IV administration of each of these substances to rats.…”

“…Recently, we successfully obtained ISF samples directly from a pore on the skin using dissolving microneedles (DMNs) [10,11] and determined the total concentrations of azithromycin (AZM), a 15-membered ring macrolide antibiotic agent, in the ISF of the skin of rats [12]. Our results indicated that the high concentrations of AZM maintained in the ISF and skin are related to its potent antibiotic effects, whereas prolonged subinhibitory AZM levels at the target site contribute to the risk of AMR emergence.…”