PHARMACOGENETIC EXPLANATION FOR EXCESSIVE BETA-BLOCKADE FOLLOWING TIMOLOL EYE DROPS - POTENTIAL FOR ORAL-OPHTHALMIC DRUG-INTERACTION

Objective.-To determine whether the effects of topically administered timolol in an individual would be dependent on the presence or absence in that individual of the P-450 enzyme CYP2D6 and whether the effects of topically administered timolol would be increased and its metaboli sm decreased by the oral administration of quinidine, a known inhibito r of CYP2D6. Design,-Single-blind randomized crossover comparison of t opical timolol, placebo, and the effects of inhibition of timolol meta bolism by oral quinidine. Setting.-Clinical research center of an acad emic medical center. Participants.-Eight male extensive metabolizers ( EMs) and five male poor metabolizers (PMs) of debrisoquin. Interventio n.-Two drops of 0.5% timolol or artificial tears were administered int o each nostril in random order, and placebo or 50 mg of quinidine was administered orally to the EMs in random order, followed 30 minutes la ter by either the timolol or placebo drops. Main Outcome Measurement.- Plasma timolol concentrations were measured by high-pressure liquid ch romatography, while the extent of P-blockade was determined by the sup pression of exercise-induced rise in heart rate. Results.-The exercise heart rate was reduced following timolol eye drops compared with plac ebo in both EMs (P<.001) and PMs (P<.001) with significantly greater h eart rate reduction (P=.01) and higher plasma timolol concentration in PMs compared with EMs (P=.03). Administration of quinidine with timol ol eye drops to EMs resulted in a further significant reduction in hea rt rate (P=.02) and increase in plasma timolol concentration (P=.04). Conclusions.-An individual's debrisoquin phenotype is an important det erminant of beta-blockade following timolol eye drops, and metabolism of timolol is inhibited and beta-blockade increased by coadministratio n of oral quinidine. Clinicians should be aware of the potential for d rug interactions that occur when orally administered drugs inhibit the metabolism of a topically administered drug.