Pharmacokinetic and pharmacodynamic analysis of systemic effect of topically applied timolol maleate ophthalmic gelling vehicle (Rysmon TG).
OBJECTIVE
The objective of this study was to evaluate the degree of systemic absorption and the systemic side effect after instillation of timolol maleate ophthalmic gelling vehicle in human.


METHODS
A volunteer study was employed, and a randomized crossover design with the two phases was used. In one phase, the volunteers instilled a single drop of the 0.5% timolol maleate ophthalmic gelling vehicle; in the other phase, the volunteers instilled a single drop of the 0.5% timolol maleate ophthalmic solution. The plasma concentration of timolol and the heart rates were studied during the following 120 min and 60 min, respectively.


RESULTS
The area under the blood concentration time curve (AUC) in timolol maleate ophthalmic gelling vehicle was lower than that in timolol maleate ophthalmic solution (p < 0.05). No differences were observed in heart rates between ophthalmic gelling vehicle and ophthalmic solution. The correlation between the calculated occupancy of beta-adrenergic receptors and the systemic side effects after instillation could be successfully analyzed with a pharmacokinetic and pharmacodynamic model, showing the predictability of the model for the systemic side effects of timolol.


CONCLUSIONS
The result of our analysis clearly shows that timolol maleate ophthalmic gelling vehicle reduced the systemic absorption below that of ophthalmic solution, but the degree in difference of systemic effects was negligible.
Ohno
Yoshiyuki
Y
Department of Pharmacy, University of Tokyo Hospital, University of Tokyo, Tokyo 113-8655, Japan. yohno-tky@umin.ac.jp
Iga
Tatuji
T
Yamada
Yasuhiko
Y
Nagahara
Miyuki
M
Araie
Makoto
M
Takayanagi
Risa
R
D000042:Absorption; D000287:Administration, Topical; D000319:Adrenergic beta-Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D019540:Area Under Curve; D003315:Cornea / Q000378:metabolism; D018592:Cross-Over Studies; D004337:Drug Carriers; D005782:Gels; D006339:Heart Rate; D006801:Humans; D008297:Male; D011817:Rabbits; D013999:Timolol / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D004337:Drug Carriers; D005782:Gels; D013999:Timolol