Drug interaction between cimetidine and timolol ophthalmic solution: Effect on heart rate and intraocular pressure in healthy Japanese volunteers

Systemic adverse effects of timolol ophthalmic solution given at usual therapeutic doses have been well characterized. Timolol is partially metabolized by cytochrome P450 (CYP) 2D6. Cimetidine inhibits the activity of cytochrome P450, including CYP2D6, leading to reduced systemic clearance of concomitant drugs. Coadministration of cimetidine has been speculated to affect the pharmacological effects of timolol ophthalmic solution, resulting in increased blood concentration. To evaluate whether administration of cimetidine with timolol ophthalmic solution increased the degree of beta-blockade, 12 healthy Japanese male volunteers ages 19 to 26 received cimetidine (400 mg), an oral placebo, timolol maleate 0.5% (0.05 mL to each eye), or placebo eye drops in a randomized, double-blind, Latin-square design. The oral drug alone was given for 3 days, and on the 4th day eye drops were applied after oral drug administration. At baseline and 1, 3, and 6 hours after eye drop administration, blood pressure and heart rate (HR) were measured before and after exercise. Intraocular pressure (IOP) was measured at rest. A visual analog scale (VAS) was used to assess subjective bodily feelings in exercise tolerance after every physical exercise. The exercise HR, exercise systolic blood pressure (SBP), and resting SBP were reduced following timolol with and without cimetidine compared with the placebo (p < 0.01, respectively). Administration of cimetidine with timolol ophthalmic solution resulted in additional reductions of the resting HR and IOP. VAS detected a significant reduction in exercise tolerance fi om timolol ophthalmic solution (p < .05). In conclusion, administration of cimetidine with timolol ophthalmic solution increased the degree of beta-blockade. Journal of Clinical Pharmacology 2000;40:193-199 (C)2000 the American College of Clinical Pharmacology.