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

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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 .cntdot. hr/ml; P < 0.01) and a twofold difference in mean t1/2 (7.5 .+-. 3 vs. 3.7 .+-. 1.7 hours; P < 0.01), reflecting differences in oral clearance (13.1 .+-. 7.8 vs. 48.5 .+-. 23.2 L/hr; P < 0.01). The degree of .beta.-blockade was greater in PMs than in EMs at 12 hours (30.9% vs. 18.2%; P < 0.05) and at 24 hours (28.3% vs. 13.1%; P < 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.

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