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 ther apeutic doses have been well characterized. Timolol is partially metabolize d by cytochrome P450 (CYP) 2D6. Cimetidine inhibits the activity of cytochr ome P450, including CYP2D6, leading to reduced systemic clearance of concom itant drugs. Coadministration of cimetidine has been speculated to affect t he pharmacological effects of timolol ophthalmic solution, resulting in inc reased blood concentration. To evaluate whether administration of cimetidin e with timolol ophthalmic solution increased the degree of beta-blockade, 1 2 healthy Japanese male volunteers ages 19 to 26 received cimetidine (400 m g), 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 dru g alone was given for 3 days, and on the 4th day eye drops were applied aft er oral drug administration. At baseline and 1, 3, and 6 hours after eye dr op administration, blood pressure and heart rate (HR) were measured before and after exercise. Intraocular pressure (IOP) was measured at rest. A visu al analog scale (VAS) was used to assess subjective bodily feelings in exer cise tolerance after every physical exercise. The exercise HR, exercise sys tolic blood pressure (SBP), and resting SBP were reduced following timolol with and without cimetidine compared with the placebo (p < 0.01, respective ly). Administration of cimetidine with timolol ophthalmic solution resulted in additional reductions of the resting HR and IOP. VAS detected a signifi cant 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 Pharmac ology 2000;40:193-199 (C)2000 the American College of Clinical Pharmacology .