Characterization of ocular pharmacokinetics of beta-blockers using a diffusion model after instillation.
OBJECTIVE
To characterize the ocular pharmacokinetics of beta-blockers (timolol and tilisolol) after instillation in the albino rabbit using a mathematical model that includes a diffusion process.


METHODS
The disposition of fluorescein isothiocyanate-dextran (FITC-dextran, molecular weight 4400), timolol, and tilisolol was determined in tear fluid and aqueous humor after instillation or ocular injection in rabbits. The in vivo penetration parameters were estimated by fitting the concentration-time profiles to the Laplace equations based on a diffusion model using MULTI(FILT) program. The in vitro permeability of drugs was measured across cornea using a two-chamber diffusion cell.


RESULTS
Concentration-time profiles of drugs in the tear fluid after instillation showed a monoexponential curve. Although a monoexponential curve was observed in the aqueous humor concentration of FITC-dextran after injection into the aqueous chamber, timolol and tilisolol showed a biexponential curve. On the basis of these results, an in vivo pharmacokinetic model was developed for estimation of penetration parameters. The in vitro partition parameters were higher than those of the in vivo parameters.


CONCLUSIONS
The ocular absorption of timolol and tilisolol was characterized using an in vivo pharmacokinetic model and in vivo penetration parameters.
Yamamura
K
K
School of Pharmaceutical Sciences, Nagasaki University, Nagasaki City, Japan.
Sasaki
H
H
Nakashima
M
M
Ichikawa
M
M
Mukai
T
T
Nishida
K
K
Nakamura
J
J
D000042:Absorption; D000287:Administration, Topical; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000465:Algorithms; D000818:Animals; D000867:Anterior Chamber / Q000378:metabolism; D001082:Aqueous Humor / Q000378:metabolism; D003315:Cornea / Q000378:metabolism; D003911:Dextrans; D004058:Diffusion; D005123:Eye / Q000378:metabolism*; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D007546:Isoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics; D008954:Models, Biological; D011817:Rabbits; D013999:Timolol / Q000008:administration & dosage / Q000493:pharmacokinetics
D000319:Adrenergic beta-Antagonists; D003911:Dextrans; D007546:Isoquinolines; C015219:fluorescein isothiocyanate dextran; D013999:Timolol; D016650:Fluorescein-5-isothiocyanate; C036593:tilisolol