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In vitro transcorneal diffusion of the antimicrobial macrolides azithromycin and clarithromycin and the impact on
Armorel D van Eyk1, Heiner I Seifart, David Meyer
1Division of Pharmacology, Department of Medicine, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa. armorel.vaneyk@wits.co.za
Purpose:
To compare the in vitro penetration of azithromycin and clarithromycin across both human and rabbit corneas.
Methods:
In vitro diffusion studies were performed on frozen-thawed (liquid nitrogen, -80 degrees C) corneas using a flow-through diffusion apparatus (24 hours, 20 degrees C, 1.5 mL/h). Either phosphate-buffered saline (PBS) or 2 mg/g polyacrylic acid (Teargel) formulations of clarithromycin and azithromycin (1 or 4 mg/mL) were used in the donor chambers. Effluent samples collected (2 hours) were analyzed using binary high-performance liquid chromatography in conjunction with either UV/VIS or tandem mass spectrometry detection.
Results:
The flux values of azithromycin (PBS and polyacrylic acid) across both types of corneas showed concentration dependence. Polyacrylic acid formulations showed a decrease in flux values of azithromycin across both types of corneas. For clarithromycin, flux values across both types of corneas were approximately 2.3-2.4 times higher than azithromycin. The flux values of azithromycin at 4 mg/mL (PBS and polyacrylic acid) across human cornea were higher than those across rabbit cornea, whereas the inverse was true at 1 mg/mL PBS for both drugs.
Conclusions:
Both macrolides penetrated the corneas, and the flux values were found to be concentration dependent (azithromycin). Clarithromycin had a higher diffusion rate across corneas than azithromycin. Although the human cornea had a higher permeability to azithromycin at a higher concentration, the inverse was found at lower concentrations for both drugs. Rabbit cornea can be used in general as an in vitro permeability model for human cornea; however, care must be taken with the extrapolation of results.
Insights
Clarithromycin demonstrated higher corneal penetration than azithromycin in vitro. Rabbit corneas can model human corneal permeability, but results require careful interpretation.
Area of Science:
- Ophthalmology
- Pharmacology
- Biomedical Engineering
Background:
- Macrolide antibiotics are crucial for treating ocular infections.
- Understanding corneal penetration is vital for optimizing drug delivery and efficacy.
- Azithromycin and clarithromycin are commonly used macrolides with differing physicochemical properties.
Purpose of the Study:
- To compare the in vitro corneal penetration of azithromycin and clarithromycin.
- To evaluate the influence of formulation (PBS vs. polyacrylic acid) on penetration.
- To assess the suitability of rabbit cornea as a model for human corneal permeability.
Main Methods:
- In vitro diffusion studies utilizing a flow-through apparatus with human and rabbit corneas.
- Application of azithromycin and clarithromycin in phosphate-buffered saline (PBS) or polyacrylic acid (Teargel) formulations.
- Analysis of drug concentrations in effluent samples via high-performance liquid chromatography (HPLC) with UV/VIS or mass spectrometry detection.
Main Results:
- Corneal flux of azithromycin was concentration-dependent and influenced by formulation.
- Clarithromycin exhibited significantly higher corneal penetration rates (2.3-2.4 times) compared to azithromycin.
- Human cornea showed higher azithromycin permeability at 4 mg/mL, while rabbit cornea showed higher permeability at 1 mg/mL for both drugs.
Conclusions:
- Both azithromycin and clarithromycin penetrate the cornea, with clarithromycin showing superior diffusion.
- Corneal permeability is concentration-dependent for azithromycin.
- Rabbit cornea serves as a viable in vitro model for human corneal permeability, though extrapolation requires caution.
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