Evaluation of the intravenous and topical routes for ocular delivery of hesperidin and hesperetin.
OBJECTIVE
The objective of this study was to determine the ocular bioavailability of hesperidin and hesperetin, especially with respect to their distribution into the posterior segment of the eye, following systemic and topical administration in rabbits.


METHODS
Hesperidin and hesperetin were administered either intravenously or topically to male New Zealand white (NZW) rabbits. Vitreous humor and plasma samples were collected after intravenous administration and analyzed to estimate the concentrations of the parent compounds and their metabolites. Ocular tissue concentrations, obtained on topical administration of hesperidin and hesperetin, were also determined.


RESULTS
In the systemic circulation, hesperidin and hesperetin were rapidly metabolized into their glucuronides, which are extremely hydrophilic in nature. Vitreal samples did not demonstrate any detectable levels of hesperidin/hesperetin following intravenous administration. Topical administration produced significant concentrations of hesperidin/hesperetin in all the ocular tissues tested at the 1 and 3 hours time points postdosing, with hesperetin showing higher levels compared to hesperidin. However, only low levels were generated in the vitreous humor. Inclusion of a penetration enhancer, benzalkonium chloride (BAK), improved the back-of-the-eye hesperetin levels.


CONCLUSIONS
Ocular delivery of hesperidin/hesperetin via the systemic route does not seem to be feasible considering the rapid generation of the hydrophilic metabolites. Topical application appears to be more promising and needs to be further developed/refined.
Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, University, Mississippi 38677, USA.
Ramesh
R
Srirangam
Ketan
K
Hippalgaonkar
Bharathi
B
Avula
Ikhlas A
IA
Khan
Soumyajit
S
Majumdar
D060433:Administration, Ophthalmic; D000818:Animals; D001548:Benzalkonium Compounds / Q000737:chemistry*; D001682:Biological Availability; D016503:Drug Delivery Systems; D005079:Excipients / Q000737:chemistry*; D005240:Feasibility Studies; D020719:Glucuronides / Q000378:metabolism; D006569:Hesperidin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D057927:Hydrophobic and Hydrophilic Interactions; D007275:Injections, Intravenous; D008297:Male; D011817:Rabbits; D013997:Time Factors; D014822:Vitreous Body / Q000378:metabolism
D001548:Benzalkonium Compounds; D005079:Excipients; D020719:Glucuronides; D006569:Hesperidin; C013015:hesperetin