Clinical pharmacologic observations on timolol. I. Disposition and effect in relation to plasma level in normal individuals.

The disposition profiles of a new beta-adrenergic blocking drug, timolol, were investigated at 11 different times in normal individuals after a single oral dose. The disposition of timolol follows first-order kinetics and may be adequately described by a one-compartment model. The pharmacokinetic data were not significantly different among the three dose levels examined. After the single oral doses, overall elimination half-life was 3.2 +/- 0.2 hours (mean +/- S.E.M.), with an observed peak time of 2.0 +/- 0.2 hours; extrapolated volume of distribution was 1.81 +/- 0.15 liter/kg; and the total plasma clearance was 557 +/- 61 ml/min. Approximately 20 per cent of elimination from the human body was dependent on the kidney. The area under the curve from zero to infinity and the peak concentration observed were dose dependent. A linear relationship was found between timolol plasma concentrations and beta-adrenergic blocking effects (per cent inhibition), as estimated from exercise-induced tachycardia. Timolol is a beta blocker which must await further clinical trials for the assessment of therapeutic implications in relation to plasma levels.