Pharmacokinetics and beta-blocking effects of timolol in poor and extensive metabolizers of debrisoquin

Abstract

We studied the pharmacokinetics and beta-blocking effects of a single, oral 20 mg dose of timolol in six poor metabolizers (PMs) and six extensive metabolizers (EMs) of debrisoquin. The plasma timolol concentration was significantly higher in PMs than in EMs. There was a fourfold difference in mean AUC (1590 +/- 1133 vs. 394 +/- 239 ng X hr/ml; P less than 0.01) and a twofold difference in mean t1/2 (7.5 +/- 3 vs. 3.7 +/- 1.7 hours; P less than 0.01), reflecting differences in oral clearance (13.1 +/- 7.8 vs. 48.5 +/- 23.2 L/hr; P less than 0.01). The degree of beta-blockade was greater in PMs than in EMs at 12 hours (30.9% vs. 18.2%; P less than 0.05) and at 24 hours (28.3% vs. 13.1%; P less than 0.05). In the group as a whole the metabolic ratio correlated positively with both kinetic data and beta-blockade, but some overlap was observed. Hence timolol metabolism appears to be subject to debrisoquin-type polymorphism, which results in interphenotypic variation in plasma concentration and beta-blocking effect.

Timolol metabolism and debrisoquine oxidation polymorphism: a population study.

“…The higher plasma timolol concentrations observed in PMs confirm earlier findings of Lewis et al (1985) and McGourty et al (1985a). However, the considerable overlap between phenotypic groups suggests that maximum separation may not be achieved at 2 h after dosing.…”

“…Two independent panel studies have shown that the pharmacokinetics and 1-adrenoceptor antagonist activity of timolol are related to debrisoquine oxidation phenotype (Lewis et al, 1985;McGourty et al, 1985a). The mean areas under the plasma drug concentration time-curve were two to four times higher in poor metabolisers (PMs) than in extensive metabolisers (EMs) of debrisoquine.…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…Timolol is a nonselective ␤-blocker that is metabolized largely by CYP2D6. PMs have a 2-to 4-fold higher mean AUC and increased and prolonged ␤-blockade after oral administration (Lewis et al, 1985;McGourty et al, 1985a). ␤-Blockade can occur with very low plasma concentrations of timolol , and ocular administration has been associated with systemic side effects (van der Zanden et al, 2001).…”

Pharmacogenomics of Open-Angle Glaucoma

“…For example, timolol is metabolized by cytochrome P40 2D6 (CYP2D6). Polymorphisms in this gene are associated with reduced efficacy of oral timolol in patients with systemic hypertension (McGourty et al, 1985). In a series of 19 OAG patients and 18 volunteers, poor metabolizers of CYP2D6 demonstrated higher systemic concentrations of ophthalmic timolol, suggesting a potential safety concern in these patients (Nieminen et al, 2005).…”