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 metabolism decreased by the oral administration of quinidine, a known inhibitor of CYP2D6.


METHODS
Single-blind randomized crossover comparison of topical timolol, placebo, and the effects of inhibition of timolol metabolism by oral quinidine.


METHODS
Clinical research center of an academic medical center.


METHODS
Eight male extensive metabolizers (EMs) and five male poor metabolizers (PMs) of debrisoquin.


METHODS
Two drops of 0.5% timolol or artificial tears were administered into each nostril in random order, and placebo or 50 mg of quinidine was administered orally to the EMs in random order, followed 30 minutes later by either the timolol or placebo drops.


METHODS
Plasma timolol concentrations were measured by high-pressure liquid chromatography, while the extent of beta-blockade was determined by the suppression of exercise-induced rise in heart rate.


RESULTS
The exercise heart rate was reduced following timolol eye drops compared with placebo in both EMs (P < .001) and PMs (P < .001) with significantly greater heart rate reduction (P = .01) and higher plasma timolol concentration in PMs compared with EMs (P = .03). Administration of quinidine with timolol eye drops to EMs resulted in a further significant reduction in heart rate (P = .02) and increase in plasma timolol concentration (P = .04).


CONCLUSIONS
An individual's debrisoquin phenotype is an important determinant of beta-blockade following timolol eye drops, and metabolism of timolol is inhibited and beta-blockade increased by coadministration of oral quinidine. Clinicians should be aware of the potential for drug interactions that occur when orally administered drugs inhibit the metabolism of a topically administered drug.
D000284:Administration, Oral; D000287:Administration, Topical; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000328:Adult; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D003647:Debrisoquin / Q000378:metabolism*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005080:Exercise Test; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000235:genetics; D009883:Ophthalmic Solutions; D010641:Phenotype; D011802:Quinidine / Q000008:administration & dosage / Q000494:pharmacology*; D016037:Single-Blind Method; D013999:Timolol / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D009883:Ophthalmic Solutions; D013999:Timolol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine; D003647:Debrisoquin