title: Pharmacokinetics of topical beta-adrenergic antagonists in rabbit aqueous humor evaluated with the microdialysis method.
abstract: The microdialysis method was used to evaluate the pharmacokinetics of the beta-adrenergic antagonists carteolol and timolol and the new ophthalmic solution WP-934 in rabbit aqueous humor, following instillation. A probe with a microdialysis membrane (length, 5 mm; diameter, 0.2 mm) was implanted in the anterior chamber of the pigmented rabbit and perfused with Ringer's solution. Twenty microliters of 0.5% timolol maleate (0.5% Timoptol(R)), 2% carteolol hydrochloride (2% Mikelan(R)), or a novel preparation of 0.5% timolol maleate (WP-934) that gels after instillation were then instilled. The concentrations of these drugs in dialysates were measured using high-performance liquid chromatography and an electrochemical detection system. In vitro relative recovery of the membrane with timolol and carteolol was approximately 17.5% and 21. 6%, respectively. Timolol and carteolol levels in aqueous humor increased rapidly after instillation of Timoptol and Mikelan and reached maximal levels (Cmax) within 60 minutes. The Cmax of carteolol (4.25 microg ml-1) was lower than that of timolol (5.52 microg ml-1), suggesting that the corneal permeability of timolol is higher than that of carteolol. After instillation of WP-934, the Cmax of timolol (12.32 microg ml-1) was 2.2-fold higher than that after instillation of Timoptol. However, t1/2 values of beta-adrenergic antagonists after instillation of the three preparations were not significantly different. These data suggest that the microdialysis technique is useful for continuous monitoring of aqueous levels of beta-blockers and for analysis of their pharmacokinetic parameters while requiring much fewer animals than conventional sampling with paracentesis.
authors.affiliation: Department of Ophthalmology, Showa University School of Medicine, 1-5-8 Hatanodai, Tokyo, Shinagawa-ku, 142-0064, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Ohtori
authors.forename: H
authors.initials: H
authors.lastname: Sato
authors.forename: S
authors.initials: S
authors.lastname: Fukuda
authors.forename: T
authors.initials: T
authors.lastname: Ueda
authors.forename: R
authors.initials: R
authors.lastname: Koide
authors.forename: Y
authors.initials: Y
authors.lastname: Kanda
authors.forename: Y
authors.initials: Y
authors.lastname: Kiuchi
authors.forename: K
authors.initials: K
authors.lastname: Oguchi
mesh_terms: D000287:Administration, Topical; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism*; D002354:Carteolol / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D011817:Rabbits; D013997:Time Factors; D013999:Timolol / Q000493:pharmacokinetics*
chemical_list: D000319:Adrenergic beta-Antagonists; D013999:Timolol; D002354:Carteolol