Systemic bioavailability and cardiopulmonary effects of 0.5% timolol eyedrops.
BACKGROUND
To investigate the pharmacological basis of systemic side effects of ophthalmic timolol, we estimated the systemic bioavailability of 0.5% timolol eyedrops and compared cardiopulmonary effects of intravenous and ophthalmic timolol.


METHODS
In a randomized crossover study we administered 0.2 mg timolol either intravenously or ocularly to eight healthy volunteers. After drug administration we measured heart rate, arterial blood pressure, forced expiratory volume in 1s, forced vital capacity, and intraocular pressure (IOP). Plasma timolol concentrations were determined using a beta-adrenoceptor binding assay.


RESULTS
The peak concentration of ophthalmic timolol in plasma, (C(max)=1.14+/-0.34 ng/ml, mean+/-SD, n=8) was measured in most subjects within 15 min after drug administration. The mean area under the curve from zero to infinitum (AUC(0-)(infinity)) was 6.46+/-2.49 ng/ml per hour after intravenous and 4.78+/-1.90 ng/ml per hour (means+/-SD, n=8) after ocular administration. The systemic bioavailability (F) of the eyedrop was 78.0+/-24.5% (mean+/-SD, n=8). Heart rate, arterial blood pressure, and pulmonary functions were similar after intravenous and ocular timolol administration, whereas IOP was lowered more effectively by the ophthalmic than the intravenous dose.


CONCLUSIONS
Ophthalmic timolol resembled intravenous timolol in terms of systemic bioavailability, plasma kinetics, and cardiopulmonary effects. Clinicians should pay attention to the high systemic bioavailability of ophthalmic timolol, because intensive systemic beta-blockade can be highly hazardous to aged patients suffering from cardiopulmonary diseases.
Korte
Juha-Matti
JM
Department of Ophthalmology, University of Turku, Kiinamyllynkatu 4-8, 20520 Turku, Finland. matti.saari@tyks.fi
Kaila
Timo
T
Saari
K Matti
KM
D000042:Absorption; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D005123:Eye / Q000378:metabolism; D005260:Female; D005541:Forced Expiratory Volume; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D009883:Ophthalmic Solutions / Q000493:pharmacokinetics; D013999:Timolol / Q000493:pharmacokinetics*; D014797:Vital Capacity
D000319:Adrenergic beta-Antagonists; D009883:Ophthalmic Solutions; D013999:Timolol