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Timolol metabolism and debrisoquine oxidation polymorphism: a population study
M S Lennard1, R V Lewis, L A Brawn
1University Department of Pharmacology and Therapeutics, Royal Hallamshire Hospital, Sheffield.
British Journal of Clinical Pharmacology
|April 1, 1989
Summary
Timolol metabolism, the breakdown of timolol (T) into ethanolamine (TE) and glycine (TG) products, is partly controlled by the debrisoquine-type genetic pathway. This impacts timolol plasma concentrations in patients.
Area of Science:
- Pharmacogenetics
- Drug Metabolism
- Cardiovascular Pharmacology
Background:
- Timolol is an antihypertensive medication.
- Understanding timolol metabolism is crucial for optimizing its therapeutic use.
- Genetic variations can influence drug metabolism and patient response.
Purpose of the Study:
- To investigate the metabolic pathways of orally administered timolol.
- To determine if timolol metabolism is influenced by genetic factors, specifically the debrisoquine-type metabolic pathway.
- To correlate urinary metabolic ratios with timolol metabolite levels.
Main Methods:
- Studied the metabolism of timolol in 108 hypertensive patients.
- Analyzed urinary debrisoquine/4-hydroxy-debrisoquine ratios.
- Measured plasma concentrations of timolol and its metabolites (TE, TG).
- Correlated urinary and plasma levels with genetic metabolic status.
Main Results:
- Found significant correlations between urinary debrisoquine ratios and timolol/metabolite ratios (T/TE, T/TG, T/TE+TG).
- Timolol metabolic ratios were higher in poor debrisoquine metabolizers (PMs), suggesting genetic control.
- Plasma timolol concentrations were approximately double in PMs compared to extensive metabolizers.
Conclusions:
- Timolol metabolism is partly under the monogenic control of the debrisoquine-type pathway.
- Genetic variations in debrisoquine metabolism affect timolol pharmacokinetics.
- The clinical significance of altered timolol plasma concentrations in poor metabolizers requires further investigation.