In Vitro Diffusion of the Immunosuppressant Tacrolimus Through Human and Rabbit Corneas

Abstract

Percentages of total TAC at the 24-h time points were approximately 4.9x and 4.1x higher than those found previously for cyclosporin A across human and rabbit corneas, respectively. Rabbit corneas are a suitable model for human corneas in in vitro permeability studies.

In Vitro Transcorneal Diffusion of the Antimicrobial Macrolides Azithromycin and Clarithromycin and the Impact on Microbial Keratitis

“…[20][21][22][23][24] The diffusion of any permeant molecule across a biological membrane is concentration driven, and smaller molecules tend to diffuse at higher rates than larger molecules. 23,24 As can be seen from the results, a higher mean steady-state flux rate was achieved for the higher concentration of azithromycin (4 mg/mL in both PBS and polyacrylic acid) across both types of cornea as opposed to a lower concentration (1 mg/mL in PBS and polyacrylic acid), thus demonstrating a dose effect. Unfortunately, solubility limitations of clarithromycin at 4 mg/mL in PBS, and in polyacrylic acid, precluded the use of these concentrations in the permeability experiments.…”

“…Apart from molecular size, the diffusion of a permeant molecule across a biological membrane (eg, the cornea of the eye) also depends on its other physicochemical properties (eg, lipophilicity, shape, polar surface area, and hydrogen bonding capacity) and the characteristics of the membrane itself. [20][21][22][23][24] The cornea consists of 3 layers when describing drug diffusion: the epithelium, stroma, and endothelium. The epithelial layer constitutes the main barrier to hydrophilic molecules, whereas the stroma is the main barrier to lipophilic molecules.…”

“…Smaller, more hydrophilic molecules tend to diffuse passively between epithelial cells (paracellular), whereas more lipophilic molecules tend to diffuse passively through (transcellular) the epithelial cells. [20][21][22][23][24] The cell membrane of the epithelial cells contains proteins and lipids, which can interact with the drug molecules. The interactions that can occur would seem to be H-bonding between the drug molecules and the -COOH groups of the fatty acids and the -OH and amide groups of the ceramides.…”

“…In human corneas, Bowman membrane is 6 times thicker than that of rabbit corneas, whereas the mean human corneal thickness is 0.51 mm compared with 0.37 mm in rabbit cornea. 24 The relative diffusion pathways through the lipophilic domains in rabbit corneas are therefore shorter than those in human corneas, leading to increased flux rates of more lipophilic molecules.…”

“…20,21 Hereafter, corneas were carefully cut, so as not to damage either endothelial or epithelial surfaces, into 4-mm 2 sections and mounted in flow-through diffusion cells (exposed area 0.039 cm 2 , as previously described). [20][21][22][23][24] Permeability experiments were performed on 7 tissue replicates for each cornea, and 6 diffusion experiments were performed for each concentration of the macrolide tested. Equilibration of 10 minutes was allowed in the donor and in the acceptor compartments of the diffusion cells.…”