Intravitreal kinetics of hesperidin, hesperetin, and hesperidin G: effect of dose and physicochemical properties

Abstract

Hesperidin, a flavanone glycoside, and its aglycone hesperetin are potential candidates for the treatment of diabetic retinopathy and macular edema. The objective of this study was to delineate vitreal pharmacokinetics of hesperidin and hesperetin and the hydrophilic derivative glucosyl hesperidin (hesperidin G) following intravitreal administration in anaesthetized rabbits. Concentration changes in vitreous humor were monitored using microdialysis sampling procedure. All three molecules were administered intravitreally at three dose levels (50 µL injection volume containing 1.5, 4.5, and 15 µg of the drug, resulting in a final vitreal concentration of 1, 3, and 10 µg/mL). Vitreal microdialysis samples were collected every 20 min over a period of 10 h. All three molecules exhibited linear pharmacokinetics within the dose range tested because area under the curve and maximum concentration (C(max) ) increased linearly with increasing dose and a significant difference in the elimination parameters such as clearance or half-life was not observed. The vitreal elimination half-life of these three compounds was observed to correlate with the molecular weight and lipophilicity of the molecules. The findings from this study provide practical information that will be useful in the future design of ocular drug delivery strategies for bioflavonoids.

Figure 1

Chemical structure of A: Hesperidin; B: Hesperetin and C: Hesperidin G (Glucosyl Hesperidin)

Figure 2

Mean vitreal log concentration vs. time profile of hesperidin following intravitreal administration of hesperidin at three doses (1.5, 4.5 and 15 μg resulting in vitreal concentration of 1, 3 and 10 μg/mL, respectively). Injection volume was 50 μL. Values represent Mean ± SD (n=4).

Figure 3

Mean vitreal log concentration vs. time profile of hesperetin following intravitreal administration of hesperetin at three doses (1.5, 4.5 and 15 μg resulting in vitreal concentration of 1, 3 and 10 μg/mL, respectively). Injection volume was 50 μL. Values represent Mean ± SD (n=4).

Figure 4

Mean vitreal log concentration vs. time profile of hesperidin G following intravitreal administration of hesperidin G at three doses (1.5, 4.5 and 15 μg resulting in vitreal concentration of 1, 3 and 10 μg/mL, respectively). Injection volume was 50 μL. Values represent Mean ± SD (n=4).

Figure 5

Linear increase in vitreal pharmacokinetic parameters Cmax (A) and AUC (B) following intravitreal administration of hesperidin, hesperetin, and hesperidin G at three doses. Values represent mean ± SD