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Pharmacogenetic explanation for excessive beta-blockade following timolol eye drops. Potential for oral-ophthalmic
1Department of Pharmacology, Meharry Medical College, Nashville, Tenn, USA.
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.
Design:
Single-blind randomized crossover comparison of topical timolol, placebo, and the effects of inhibition of timolol metabolism by oral quinidine.
Setting:
Clinical research center of an academic medical center.
Participants:
Eight male extensive metabolizers (EMs) and five male poor metabolizers (PMs) of debrisoquin.
Intervention:
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.
Main Outcome Measurement:
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.
Insights
Timolol eye drops cause greater heart rate reduction in poor metabolizers due to CYP2D6 enzyme presence. Oral quinidine increases timolol effects and concentration, highlighting potential drug interactions.
Area of Science:
- Pharmacology
- Clinical Pharmacology
- Drug Metabolism
Background:
- Topical timolol is widely used for glaucoma.
- The cytochrome P450 enzyme CYP2D6 plays a role in drug metabolism.
- Individual variability in CYP2D6 activity can influence drug response.
Purpose of the Study:
- To investigate if CYP2D6 enzyme presence affects topical timolol efficacy.
- To determine if quinidine, a CYP2D6 inhibitor, alters timolol's effects and metabolism.
- To assess potential drug interactions between topical timolol and oral quinidine.
Main Methods:
- A single-blind randomized crossover study design was employed.
- Participants included extensive metabolizers (EMs) and poor metabolizers (PMs) of debrisoquin.
- Timolol eye drops were administered with or without oral quinidine, with placebo controls.
Main Results:
- Topical timolol reduced heart rate in both EMs and PMs.
- PMs exhibited greater heart rate reduction and higher plasma timolol concentrations compared to EMs.
- Oral quinidine administration to EMs significantly increased timolol's beta-blockade effect and plasma concentration.
Conclusions:
- An individual's debrisoquin phenotype significantly influences topical timolol's beta-blockade effects.
- Coadministration of oral quinidine inhibits timolol metabolism and enhances its therapeutic effect.
- Clinicians must consider potential drug interactions involving orally administered CYP2D6 inhibitors and topical medications.