Blood, Tissue, and Intracellular Concentrations of Erythromycin and Its Metabolite Anhydroerythromycin during and after Therapy

Abstract

For macrolides, clinical activity but also the development of bacterial resistance has been attributed to prolonged therapeutic and subtherapeutic concentrations. Although erythromycin is a long-established antimicrobial, concomitant determination of the pharmacokinetics of erythromycin and its metabolites in different compartments is limited. To better characterize the pharmacokinetics of erythromycin and its anhydrometabolite (anhydroerythromycin [AHE]) in different compartments during and after the end of treatment with 500 mg of erythromycin four times daily, concentration-time profiles were determined in plasma, interstitial space of muscle and subcutaneous adipose tissue, and white blood cells (WBCs) at days 1 and 3 of treatment and 2 and 7 days after end of therapy. In WBCs, concentrations of erythromycin exceeded those in plasma approximately 40-fold, while free concentrations in plasma and tissue were comparable. The observed delay of peak concentrations in tissue might be caused by fast initial cellular uptake. Two days after the end of treatment, subinhibitory concentrations were observed in plasma and interstitial space of both soft tissues, while 7 days after the end of treatment, erythromycin was not detectable in any compartment. This relatively short period of subinhibitory concentrations may be advantageous compared to other macrolides. The ratio of erythromycin over AHE on day 1 was highest in plasma (2.81 ؎ 3.45) and lowest in WBCs (0.27 ؎ 0.22). While the ratio remained constant between single dose and steady state, after the end of treatment the concentration of AHE declined more slowly than that of the parent compound, indicating the importance of the metabolite for the prolonged drug interaction of erythromycin. Macrolides account for 10 to 15% of the worldwide consumption of antibiotics (25,31). Although in many countries erythromycin has been replaced by newer relatives like azithromycin and clarithromycin, prescription of erythromycin still has a substantial place in less developed countries but also certain regions within Europe (15, 40). However, bacterial resistance against macrolides dramatically escalated in many countries during the last decades (14,23,35). Total consumption of antimicrobials on the one hand and the presence of long periods of exposure of bacterial populations to subinhibitory concentrations of antibiotics on the other hand are considered critical factors for selecting bacterial resistance (2, 3, 16).Erythromycin is known for its highly variable bioavailability after oral ingestion and its susceptibility toward degradation under acidic conditions. Although its half-life in plasma is short and the pharmacokinetic (PK) profile intraindividually heterogeneous, it is very well distributed throughout body tissues and accumulates in leukocytes (11). While clinical studies have shown the effectiveness of erythromycin in skin and soft tissue infections (33, 39), the in vivo penetration and the resulting free concentrations in interstitial space of soft tissues, i.e., the ...

Importance of Relating Efficacy Measures to Unbound Drug Concentrations for Anti-Infective Agents

“…In vivo studies provide an opportunity to evaluate drug distribution to the target site and the immune system's response to an infection. In human subjects, collection of plasma and microdialysis samples, coupled with isolation of white blood cells and subsequent determination of intracellular drug concentrations, provides an opportunity to assess tissue distribution in various compartments (68).…”

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

“…Azithromycin concentrations in plasma, microdialysate, and WBC were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in analogy to a previously published method (29). The lower limit of quantification (LLOQ) for azithromycin was 1.00 ng/ml in plasma and 0.500 ng/ml for analyses of microdialysate and WBC samples, and interday precision and accuracy were 4.6 Ϯ 2.8% and 100.3 Ϯ 3.4% (plasma) and 6.6 Ϯ 1.2% and 98.0 Ϯ 4.3% (microdialysate and WBC).…”

Effects of Acute and Chronic Exposure to Residual Level Erythromycin on Human Intestinal Epithelium Cell Permeability and Cytotoxicity

“…If withdrawal times for clearance of this antimicrobial are not strictly followed, excessive exposure to erythromycin and its metabolites to the GIT can occur, raising questions about potential effects on human health [9,10]. The PK/PD study revealed that erythromycin is metabolized into anhydroerythromycin (AHE) by gastric fluids [11]. The hydrolysis mechanism is more effective in acidic conditions compared to neutral or basic conditions.…”

“…The hydrolysis mechanism is more effective in acidic conditions compared to neutral or basic conditions. Erythromycin and AHE are differentially distributed in blood, tissue, and leukocytes during and following therapy [11]. A detectable concentration of erythromycin was present in these sites/cells 72 h after the treatment; however, the proportion of AHE becomes higher after the end of treatment.…”