In vitro transcorneal diffusion of the antimicrobial macrolides azithromycin and clarithromycin and the impact on microbial keratitis.
OBJECTIVE
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.
van Eyk
Armorel D
AD
Division of Pharmacology, Department of Medicine, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa. armorel.vaneyk@wits.co.za
Seifart
Heiner I
HI
Meyer
David
D
van der Bijl
Pieter
P
D000328:Adult; D000368:Aged; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D017963:Azithromycin / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D017291:Clarithromycin / Q000493:pharmacokinetics*; D003315:Cornea / Q000378:metabolism*; D003320:Corneal Ulcer / Q000188:drug therapy* / Q000382:microbiology; D004058:Diffusion; D015818:Eye Infections, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D008875:Middle Aged; D010539:Permeability; D011817:Rabbits; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D000900:Anti-Bacterial Agents; D017963:Azithromycin; D017291:Clarithromycin