Biopharmaceutic and Pharmacokinetic Evaluation of Hesperidin and Hesperetin for Ocular Delivery

The bioflavonoid hesperidin and its aglycone hesperetin are promising candidates for the treatment of diabetic retinopathy and diabetic macular edema because of their pharmacological properties. The objective of this project was to characterize the biopharmaceutic and pharmacokinetic characteristics of hesperidin and hesperetin for ocular delivery, especially with respect to the distribution of these compounds to the posterior segment of the eye. Hesperidin and hesperetin were found to be water insoluble compounds. Although they demonstrated good permeability across the ocular tissues, hesperetin\u27s permeability was found to be higher than that of hesperidin. Hesperidin demonstrated symmetrical transcorneal and transretinal permeation whereas hesperetin exhibited asymmetrical transcorneal and symmetrical transretinal transport. However, none of the influx or efflux transporters, expressed on the cornea, were involved in hesperetin\u27s corneal transport. It was concluded that hesperetin\u27s physicochemical properties, ultrastructure of the cornea and components of the diffusion media play a major role in the passive asymmetric transport. Results from the intravitreal kinetic studies of hesperidin, hesperetin and glucosyl-hesperidin (a water soluble derivative of hesperidin), following intravitreal injection, revealed that all three compounds have relatively short half-lives (\u3c 8h) in the vitreous humor. Hesperetin demonstrated the shortest half-life, consistent with its physiochemical characteristics. All three compounds exhibited linear pharmacokinetics, within the dose range tested. This information will be critical in the design of ocular drug delivery systems for these compounds. The ocular bioavailability studies following systemic administration suggested that vitreal bioavailability is negligible because of rapid conversion of both hesperidin and hesperetin into their hydrophilic metabolite, hesperetin-glucuronide, in the plasma. In contrast, topical instillation produced significant concentrations of hesperidin and hesperetin in the ocular tissues. Hesperetin\u27s diffusion into the ocular tissues, in vivo, was high compared to hesperidin; however, very low levels were observed in the vitreous humor. Inclusion of benzalkonium chloride, as a penetration enhancer/preservative, significantly improved the vitreal levels of hesperetin. In conclusion, topical administration would be ideal for the delivery of hesperetin to the deeper ocular tissues. Development of a controlled release drug delivery system and specialized ophthalmic formulations will reduce the frequency of administration needed to sustain the levels at the target site

Vitreal Kinetics of Quinidine in Rabbits in the Presence of Topically Coadministered P-Glycoprotein Substrates/Modulators

The purpose of this study was to investigate whether topically administered P-glycoprotein (P-gp) substrates/modulators can alter vitreal kinetics of intravitreally administered quinidine. Male New Zealand rabbits were used under anesthesia. Vitreal kinetics of intravitreally administered quinidine (0.75-μg dose) was determined alone and in the presence of verapamil (coadministered topically/intravitreally) or prednisolone hemisuccinate sodium (PHS) (coadministered topically). In the presence of topically instilled verapamil (1% w/v), elimination half-life (t1/2) (176 ± 7 min), apparent elimination rate constant (λz) (0.0039 ± 0.0001 min–1), and mean retention time (MRT) (143 ± 30 min) of intravitreally administered quinidine were significantly different from those of the control (105 ± 11 min, 0.0066 ± 0.0007 min–1, and 83 ± 13 min, respectively). A 2-fold increase in the t1/2 with a corresponding decrease in λz and a 1.5-fold increase in the MRT of quinidine were observed in the presence of topically coadministered 2% w/v PHS. Intravitreal coadministration of quinidine and verapamil resulted in a significant increase in t1/2 (159 ± 9 min) and a decrease in λz (0.0043 ± 0.0002 min–1) of quinidine. The vitreal pharmacokinetic parameters of sodium fluorescein, alone or in the presence of topically instilled verapamil, did not show any statistically significant difference, indicating that ocular barrier integrity was not affected by topical verapamil administration. Results from this study suggest that topically applied P-gp substrates/modulators can alter vitreal pharmacokinetics of intravitreally administered P-gp substrates, possibly through the inhibition of P-gp expressed on the basolateral membrane of the retinal pigmented epithelium

Interaction between Topically and Systemically Coadministered P-Glycoprotein Substrates/Inhibitors: Effect on Vitreal Kinetics

The objective of the present study was to investigate the effect of topically coadministered P-glycoprotein (P-gp) substrates/inhibitors on the vitreal kinetics of a systemically administered P-gp substrate. Anesthetized male rabbits were used in these studies. The concentration-time profile of quinidine in the vitreous humor, after intravenous administration, was determined alone and in the presence of topically coadministered verapamil, prednisolone sodium phosphate (PP), and erythromycin. The vitreal pharmacokinetic parameters of quinidine in the presence of verapamil [apparent elimination rate constant (λz), 0.0027 ± 0.0002 min−1; clearance (CL_F), 131 ± 21 ml/min; area under the curve (AUC0–∞), 39 ± 7.0 μg · min/ml; and mean residence time, 435 ± 20 min] were significantly different from those of the control (0.0058 ± 0.0006 min−1, 296 ± 46 ml/min, 17 ± 3 μg · min/ml, and 232 ± 20 min, respectively). A 1.7-fold decrease in the vitreal λz and a 1.5-fold increase in the vitreal AUC of quinidine were observed in the presence of topical PP. Statistically significant differences between the vitreal profiles of the control and erythromycin-treated group were also observed. Plasma concentration-time profiles of quinidine, alone or in the presence of the topically instilled compounds, remained unchanged, indicating uniform systemic quinidine exposure across groups. This study demonstrates an interaction between topically and systemically coadministered P-gp substrates, probably through the modulation of P-gp on the basolateral membrane of the retinal pigmented epithelium, leading to changes in the vitreal kinetics of the systemically administered agent