Ocular pharmacokinetics of topically-applied ketoconazole solution containing hydroxypropyl beta-cyclodextrin to rabbits.
OBJECTIVE
The aim of this study was to develop an aqueous ketoconazole (KET) eye drop in order to increase the corneal permeability and improve ocular bioavailability following topical application.


METHODS
Hydroxypropyl beta-cyclodextrin (HP-beta-CD) was used to formulate an aqueous eye drop to improve the aqueous solubility of KET. A single dose of of either KET suspension (1.5%; KET-SP) or KET (1.5%)/HP-beta -CD (12.5%) solution (KET-CD) was applied to rabbits. Aqueous humor and cornea were collected after 5, 10, 20, 30, 45, 60, 90, 120, and 180 min. KET concentrations were determined by high-performance liquid chromatography after extraction.


RESULTS
After topically applying KET-CD, the KET concentrations in aqueous humor were significantly increased at 10 approximately 120 min, compared with those of KET-SP (P < 0.05), whereas KET concentrations became undectable at 180 min after topically applying KET-SP. The highest levels of KET in aqueous humor (Cmax, 2.67 microg/mL) were obtained after a 20-min application of KET-CD, 6.1 times greater than that corresponding to the KET-SP at 30 min. The KET concentrations in aqueous humor for post-120- and 180-min instillations of KET-CD were 57.9 and 34.5 times higher than that of KET-SP post-120 min, respectively. The KET-CD produced an over eightfold bioavailability (AUC(0-120), area under the concentration-time curve between 0 and 120 min) increase in aqueous humor over the KET-SP. Peak KET concentration in the cornea (118.24 microg/g) was achieved within 5 min after the instillation of KET-CD, 18.4 times higher than that of KET-SP at the same time point, whereas the highest KET level in cornea was only 8.57 microg/g after a 10-min application of KET-SP. The KET levels in corneas obtained after the application of KET-CD were all much higher than those obtained by KETSP (P < 0.01). The KET-CD produced an over twelvefold bioavailability (AUC(0-120)) increase in corneas over the KET-SP.
Zhang
Junjie
J
Pharmaceutic and Pharmacology Department, Henan Eye Institute, Henan Key Laboratory of Keratopathy, Zhengzhou, China. zhangjj06@yahoo.com.cn
Wang
Liya
L
Gao
Changfeng
C
Zhang
Li
L
Xia
Huiyun
H
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000287:Administration, Topical; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001082:Aqueous Humor / Q000378:metabolism; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D003315:Cornea / Q000378:metabolism; D004337:Drug Carriers; D005123:Eye / Q000378:metabolism; D007654:Ketoconazole / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D009883:Ophthalmic Solutions; D010539:Permeability; D011817:Rabbits; D012995:Solubility; D014018:Tissue Distribution; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
D000935:Antifungal Agents; D004337:Drug Carriers; D009883:Ophthalmic Solutions; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D007654:Ketoconazole