Pharmacokinetic differences between single and multiple oral dosing with the guidance for beta-adrenoceptor blockade assessment.

The disposition profiles of a new beta-adrenergic-blocking drug, timolol, were investigated in healthy subjects after single oral doses, and in patients with mild or moderate essential hypertension given multiple doses. The t1/2 of timolol were different between the two groups, possibly due to the decreased plasma clearance after multiple administration. The dosage regimen calculations for patients indicated to receive the treatment for certain chronic diseases, should be determined by utilizing the disposition data obtained in steady-state conditions. The absolute reduction of exercise heart rate gave the best coefficient as a beta-blockade assessment. Applying a theory for translating the pharmacokinetics to the duration-action course of drug, pharmacokinetic t1/2 was proven to be much shorter than pharmacological t1/2. Timolol given on a twice-daily schedule has shown both antihypertensive effectiveness and plasma-renin-suppressing action in different subject. However, the casual relationship between the drug plasma level, blood pressure fall and change in PRA was not so clearly disclosed. The pharmacokinetics of beta-blockers, particularly with the property of receiving extensive metabolism by the mechanism of hepatic first-pass effect should be studied between single- and multiple-dosing schedules in subjects with diverse clinical conditions.